Salts of lorcaserin with optically active acids

ABSTRACT

Salts of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with optically active acids, and pharmaceutical compositions comprising them that are useful for, inter alia, weight management.

This application is a 35 USC 371 National Stage Entry ofPCT/US2011/049935 filed Aug. 31, 2011, and claims the benefit of U.S.Provisional Application No. 61/402,580 filed Sep. 1, 2010, each of whichis incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to salts of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with opticallyactive acids, and pharmaceutical compositions comprising them that areuseful for, inter alia, weight management.

BACKGROUND OF THE INVENTION

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas type II diabetes, hypertension, stroke, cancer and gallbladderdisease.

Obesity is now a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in numbers ofobese people is due largely to the increasing preference for high fatcontent foods but also the decrease in activity in most people's lives.Currently about 30% of the population of the USA is now consideredobese.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m2). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see table below).

Classification Of Weight By Body Mass Index (BMI) BMI CLASSIFICATION<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9Obesity (Class I) 35.0-39.9 Obesity (Class II) >40   Extreme Obesity(Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that are independent of other risk factors. The most commondiseases associated with obesity are cardiovascular disease(particularly hypertension), diabetes (obesity aggravates thedevelopment of diabetes), gall bladder disease (particularly cancer) anddiseases of reproduction. The strength of the link between obesity andspecific conditions varies. One of the strongest is the link with type 2diabetes. Excess body fat underlies 64% of cases of diabetes in men and77% of cases in women (Seidell, Semin Vasc Med, 5:3-14 (2005)). Researchhas shown that even a modest reduction in body weight can correspond toa significant reduction in the risk of developing coronary heartdisease.

There are problems however with the BMI definition in that it does nottake into account the proportion of body mass that is muscle in relationto fat (adipose tissue). To account for this, obesity can also bedefined on the basis of body fat content: greater than 25% in males andgreater than 30% in females.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplications induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents would decrease by 35%. The incidence of coronarydiseases is doubled in subjects less than 50 years of age who are 30%overweight. The diabetes patient faces a 30% reduced lifespan. After age45, people with diabetes are about three times more likely than peoplewithout diabetes to have significant heart disease and up to five timesmore likely to have a stroke. These findings emphasize theinter-relations between risks factors for diabetes and coronary heartdisease and the potential value of an integrated approach to theprevention of these conditions based on the prevention of obesity(Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

The first line of treatment is to offer diet and life style advice topatients such as reducing the fat content of their diet and increasingtheir physical activity. However, many patients find this difficult andneed additional help from drug therapy to maintain results from theseefforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity because of a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of patients led to itswithdrawal by the FDA in 1998.

In addition, two drugs have been launched in the USA and Europe:Orlistat (Xenical™) a drug that prevents absorption of fat by theinhibition of pancreatic lipase, and Sibutramine (Reductil™), a5-HT/noradrenaline re-uptake inhibitor. However, side effects associatedwith these products may limit their long-term utility. Treatment withXenical™ is reported to induce gastrointestinal distress in somepatients, while Sibutramine has been associated with raised bloodpressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in physical and in psychiatric disorders.5-HT has been implicated in the regulation of feeding behavior. 5-HT isbelieved to work by inducing a feeling of satiety, such that a subjectwith enhanced 5-HT stops eating earlier and fewer calories are consumed.It has been shown that a stimulatory action of 5-HT on the 5-HT_(2C)receptor plays an important role in the control of eating and in theanti-obesity effect of d-fenfluramine. As the 5-HT_(2C) receptor isexpressed in high density in the brain (notably in the limbicstructures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVNand DMH, and predominantly in the choroid plexus) and is expressed inlow density or is absent in peripheral tissues, a selective 5-HT_(2C)receptor agonist can be a more effective and safe anti-obesity agent.Also, 5-HT_(2C) knockout mice are overweight with cognitive impairmentand susceptibility to seizure.

It is believed that the 5-HT_(2C) receptor may play a role in obsessivecompulsive disorder, some forms of depression, and epilepsy.Accordingly, agonists can have anti-panic properties, and propertiesuseful for the treatment of sexual dysfunction.

In sum, the 5-HT_(2C) receptor is a receptor target for the treatment ofobesity and psychiatric disorders, and it can be seen that there is aneed for selective 5-HT_(2C) agonists which safely decrease food intakeand body weight.

The present invention pertains to certain salts of the selective5-HT_(2C)-receptor agonist8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, andpharmaceutical compositions comprising them. Like many pharmaceuticallyuseful compounds, 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinecontains an asymmetric carbon atom and thus it can exist as differentoptical isomers. Optical isomers of pharmaceutically useful compoundsmay posses significantly different physiological activity and therefore,compounds useful for resolving mixtures of optical isomers are needed.One method of resolving pharmaceutically useful compounds containing oneor more asymmetric carbon atom is by the formation of diastereoisomericsalts. Once resolved, such salts are useful for preparing pharmaceuticalcompositions directly, without the need for further processing theresolved pharmaceutically useful compound to another salt form, or tothe free base or free acid.

One aspect of the present invention pertains to optically active acidsalts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 1), and are useful for, inter alia, weight management,including weight loss and the maintenance of weight loss. Compound 1 isdisclosed in PCT patent publication WO2003/086303, which is incorporatedherein by reference in its entirety.

Various synthetic routes to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its relatedsalts, enantiomers, crystalline forms, and intermediates, have beenreported in PCT publications, WO 2005/019179, WO 2006/069363, WO2007/120517, WO 2008/070111, WO 2009/111004, and in U.S. provisionalapplication 61/396,752 each of which is incorporated herein by referencein its entirety.

Combinations of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with otheragents, including without limitation, phentermine, and uses of suchcombinations in therapy are described in WO 2006/071740, which isincorporated herein by reference in its entirety

The following United States provisional applications are related to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine: 61/402,578;61/403,143; 61/402,580; 61/402,628; 61/403,149; 61/402,589; 61/402,611;61/402,565; 61/403,185; each of which is incorporated herein byreference in its entirety.

The following applications are related to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and have thesame filing date as the subject application: PCT/US11/49914, a PCTapplication which claims priority to United States provisionalapplications 61/402,578 and 61/403,143; PCT/US11/49936, a PCTapplication which claims priority to United States provisionalapplications 61/402,628 and 61/403,149; PCT/US11/49953, a PCTapplication which claims priority to U.S. provisional application61/402,589; PCT/US11/49960, a PCT application which claims priority toU.S. provisional application 61/402,611; and PCT/US11/49955, a PCTapplication which claims priority to United States provisionalapplications 61/402,565 and 61/403,185; each of which is incorporatedherein by reference in its entirety.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(lorcaserin hydrochloride) is an agonist of the 5-HT_(2C) receptor andshows effectiveness at reducing obesity in animal models and humans. InDecember 2009, Arena Pharmaceuticals submitted a New Drug Application,or NDA, for lorcaserin to the FDA. The NDA submission is based on anextensive data package from lorcaserin's clinical development programthat includes 18 clinical trials totaling 8,576 patients. The pivotalphase 3 clinical trial program evaluated nearly 7,200 patients treatedfor up to two years, and showed that lorcaserin consistently producedsignificant weight loss with excellent tolerability. About two-thirds ofpatients achieved at least 5% weight loss and over one-third achieved atleast 10% weight loss. On average, patients lost 17 to 18 pounds orabout 8% of their weight. Secondary endpoints, including bodycomposition, lipids, cardiovascular risk factors and glycemic parametersimproved compared to placebo. In addition, heart rate and blood pressurewent down. Lorcaserin did not increase the risk of cardiac valvulopathy.Lorcaserin improved quality of life, and there was no signal fordepression or suicidal ideation. The only adverse event that exceededthe placebo rate by 5% was generally mild or moderate, transientheadache. Based on a normal BMI of 25, patients in the first phase 3trial lost about one-third of their excess body weight. The averageweight loss was 35 pounds or 16% of body weight for the top quartile ofpatients in the second phase 3 trial.

In view of the growing demand for compounds useful in the treatment ofdisorders related to the 5-HT_(2C) receptor,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine has emergedhas an important new compound. Accordingly, new salts and pharmaceuticalcompositions of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and processesfor their preparation are needed. The salts and processes describedherein help meet these and other needs.

SUMMARY OF THE INVENTION

A priori, it is difficult to predict with confidence which salts of aparticular compound will be solid, stable, and readily isolable. Saltsof chiral amines with optically active acids are no exception. It isonly through diligent experimentation that a stable, solid-state saltmay be discovered; once that salt is in-hand however, the artisan ofordinary skill is equipped to resolve its diastereoisomers. In thecourse of preparing the salts of the present invention, manysalt-forming agents commonly used in the pharmaceutical industry (seee.g. Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977))were investigated. DL-lactate, D-gluconate, and D-lactobionate salts of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine were prepared,but in contrast to the crystalline salts of the present invention, theyfailed to crystallize.

One aspect of the present invention pertains to certain optically activeacid salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 1) and pharmaceutically acceptable solvates and hydratesthereof.

One aspect of the present invention pertains to certain optically activeacid salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineCompound 1.

One aspect of the present invention pertains to salts selected from:(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineL-glutamate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt; and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt; and pharmaceutically acceptable solvates and hydrates thereof.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a salt of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to processes for preparinga pharmaceutical composition comprising admixing a salt of the presentinvention, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to bulk pharmaceuticalcompositions suitable for the manufacture of dosage forms for weightmanagement, comprising a salt of the present invention, and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to processes for preparingbulk pharmaceutical compositions suitable for the manufacture of dosageforms for weight management, comprising admixing a salt of the presentinvention, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

One aspect of the present invention pertains to the use of salts of thepresent invention in the manufacture of a medicament for weightmanagement in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof the human or animal body by therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: PXRD of Compound 1 (1S)-(+)-10-Camsylate Salt, Form I.

FIG. 2: DSC and TGA of Compound 1 (1S)-(+)-10-Camsylate Salt, Form I.

FIG. 3: DMS of Compound 1 (1S)-(+)-10-Camsylate Salt, Form I.

FIG. 4: PXRD of Compound 1 Hemi-L-Malate Salt, Form I.

FIG. 5: DSC and TGA of Compound 1 Hemi-L-Malate Salt, Form I.

FIG. 6: DMS of Compound 1 Hemi-L-Malate Salt, Form I.

FIG. 7: PXRD of Compound 1 L-Glutamate Salt, Form I.

FIG. 8: DSC and TGA of Compound 1 L-Glutamate Salt, Form I.

FIG. 9: DMS of Compound 1 L-Glutamate Salt, Form I.

FIG. 10: PXRD of Compound 1 L-Aspartate Salt, Form I.

FIG. 11: DSC and TGA of Compound 1 L-Aspartate Salt, Form I.

FIG. 12: DMS of Compound 1 L-Aspartate Salt, Form I.

FIG. 13: PXRD of Compound 1 Hemimucate Salt, Form I.

FIG. 14: DSC and TGA of Compound 1 Hemimucate Salt, Form I.

FIG. 15: DMS of Compound 1 Hemimucate Salt, Form I.

FIG. 16: PXRD of Compound 1 Pyroglutamate Salt, Form I.

FIG. 17: DSC and TGA of Compound 1 Pyroglutamate Salt, Form I.

FIG. 18: DMS of Compound 1 Pyroglutamate Salt, Form I.

FIG. 19: PXRD of Compound 1 Glucuronate Salt, Form I.

FIG. 20: DSC and TGA of Compound 1 Glucuronate Salt, Form I.

FIG. 21: DMS of Compound 1 Glucuronate Salt, Form I.

FIG. 22: PXRD of Compound 1 Di-camphorate Salt Solvate, Form I.

FIG. 23: DSC and TGA of Compound 1 Di-camphorate Salt Solvate, Form I.

FIG. 24: DMS of Compound 1 Di-camphorate Salt Solvate, Form I.

DETAILED DESCRIPTION

It should be appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

DEFINITIONS

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonist” refers to a moiety that interacts with and activatesa receptor, such as the 5-HT_(2C) serotonin receptor, and initiates aphysiological or pharmacological response characteristic of thatreceptor.

The term “individual” refers to both humans and non-human mammals.Non-human mammals include but are not limited to rodents such as miceand rats, etc. rabbits, dogs, cats, swine, cattle, sheep, horses, andnon-human primates such as monkeys and apes, etc.

The term “pharmaceutical composition” refers to a composition comprisingat least one active ingredient; including but not limited to Compound 1and pharmaceutically acceptable salts, solvates and hydrates thereof,whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician or caregiver or by an individual, which includes one or moreof the following:

(1) Preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “treatment” as used herein refers to one or more of thefollowing:

(1) prevention of a disease, for example, prevention of a disease,condition or disorder in an individual that may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease;

(2) inhibition of a disease, for example, inhibition of a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., arresting further development of the pathology and/orsymptomatology); and

(3) amelioration of a disease, for example, amelioration of a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Whether an individual is in need of treatment is a judgment made by acaregiver (e.g. nurse practitioner, physician, physician assistant,nurse, etc. in the case of humans; veterinarian in the case of animals,including non-human mammals) that an individual or animal requires orwill benefit from treatment. This judgment is made based on a variety offactors that are in the realm of a caregiver's expertise, but thatincludes the knowledge that the individual or animal is ill, or willbecome ill, as the result of a disease, condition or disorder that istreatable by Compound 1 and pharmaceutically acceptable salts, solvatesand hydrates thereof. Accordingly, Compound 1 and pharmaceuticallyacceptable salts, solvates and hydrates thereof can be used in aprotective or preventive manner; or Compound 1 and pharmaceuticallyacceptable salts, solvates and hydrates thereof can be used toalleviate, inhibit or ameliorate a disease, condition or disorder.

The term “weight management” as used herein refers to controlling bodyweight and in the context of the present invention is directed towardweight loss and the maintenance of weight loss (also called weightmaintenance herein). In addition to controlling body weight, weightmanagement includes controlling parameters related to body weight, forexample, BMI, percent body fat and waist circumference. For example,weight management for an individual who is overweight or obese can meanlosing weight with the goal of keeping weight in a healthier range.Also, for example, weight management for an individual who is overweightor obese can include losing body fat or circumference around the waistwith or without the loss of body weight.

The term “maintenance of weight loss” or “weight maintenance” as usedherein refers to preventing, reducing or controlling weight gain afterweight loss. It is well known that weight gain often occurs after weightloss. Weight loss can occur, for example, from dieting, exercising,illness, drug treatment, surgery or any combination of these methods,but often an individual that has lost weight will regain some or all ofthe lost weight. Therefore, weight maintenance in an individual who haslost weight can include preventing weight gain after weight loss,reducing the amount of weigh gained after weight loss, controllingweight gain after weight loss or slowing the rate of weight gain afterweight loss.

The term “optically active acid salt” as used herein means a salt inwhich the anion is derived from the deprotonation of an optically activeacid. The following table provides certain non-limiting examples ofoptically active acids.

Chemical Name Structure (1S)-(+)-10- camphorsulfonic acid

L-malic acid

L-glutamic acid

L-aspartic acid

mucic acid

pyroglutamatic acid

glucuronic acid

(1R,3S)-(+)-camphoric acid

D-gluconic acid

L-lactic acid

L-tartaric acid

D-glycero-D-gulo- heptonic acid

D-lactobionic acid

L-mandelic acid

(D)-(+)-pantothenic acid

dibenzoyl-L-tartaric acid

Di-p-toluoyl-L-tartaric acid

(S)-2-phenylpropionic acid

L-N-acetylphenylalanine

(1R)-(+)-3-bromocamphor- 8-sulfonic acid

(S)-2,3- isopropylideneglycerol hemiphthalate

Diacetyl-L-tartaric acid

N-tosyl-L-glutamic acid

(1S)-(−)-Camphanic acid

The term “diastereoisomeric” as used herein refers to the relationshipbetween stereoisomers that are not enantiomers. Similarly, the term“diastereoisomeric salts” as used herein refers to the relationshipbetween salts that comprise both a chiral anion and a chiral cation,wherein the salts are stereoisomers but are not enantiomers.

For example, in a salt consisting of an anion with one chiral center anda cation with one chiral center, there are four possible stereoisomersof the salt:

-   -   A. (R)-anion-(R)-cation;    -   B. (R)-anion-(S)-cation;    -   C. (S)-anion-(R)-cation; and    -   D. (S)-anion-(S)-cation.

In this example each salt has one enantiomeric salt and twodiastereoisomeric salts. The various relationships between the foursalts above is shown in the following table:

Salt Enantiomer of salt Diastereoisomers of salt A D B and C B C A and DC B A and D D A B and C

By way of further example, in a salt consisting of an anion with twochiral centers and a cation with one chiral center, there are eightpossible stereoisomers of the salt:

-   -   E. (R,R)-anion-(R)-cation;    -   F. (R,R)-anion-(S)-cation;    -   G. (R,S)-anion-(R)-cation;    -   H. (R,S)-anion-(S)-cation;    -   I. (S,R)-anion-(R)-cation;    -   J. (S,R)-anion-(S)-cation;    -   K. (S,S)-anion-(R)-cation; and    -   L. (S,S)-anion-(S)-cation.

In this example each salt has one enantiomeric salt and sixdiastereoisomeric salts. The various relationships between the eightsalts above is shown in the following table:

Salt Enantiomer of Salt Diastereoisomers of Salt E L F, G, H, I, J, andK F K E, G, H, I, J, and L G J E, F, H, I, K, and L H I E, F, G, J, K,and L I H E, F, G, J, K, and L J G E, F, H, I, K, and L K F E, G, H, I,J, and L L E F, G, H, I, J, and KSalts of the Present Invention

The present invention is directed, inter alia, to solid, stable, andreadily isolable salts of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andpharmaceutically acceptable solvates and hydrates thereof. The solidstate properties of the crystalline forms of salts the present inventionare summarized infra.

One aspect of the present invention pertains to salts selected from:(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineL-glutamate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt; and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt; and pharmaceutically acceptable solvates and hydrates thereof.

One aspect of the present invention pertains to salts selected from:(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineL-glutamate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt; and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt; and pharmaceutically acceptable solvates and hydratesthereof.

One aspect of the present invention pertains to salts selected from:(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineL-glutamate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt; and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronatesalt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamate salt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartate salt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate salt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronate salt.

One aspect of the present invention pertains to8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphorate saltsolvate.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronatesalt.

One aspect of the present invention pertains to(±)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronatesalt.

One aspect of the present invention pertains to(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a salt of the present invention.

One aspect of the present invention pertains to process for preparing apharmaceutical composition comprising admixing a salt of the presentinvention and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt of the present invention.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for weightmanagement in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of treatment of the human or animal bodyby therapy.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight loss.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of maintenance of weight loss.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of decreasing food consumption.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of increasing meal-related satiety.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of reducing pre-meal hunger.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of reducing intra-meal food intake.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management further comprising areduced-calorie diet.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management further comprising aprogram of regular exercise.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management further comprising areduced-calorie diet and a program of regular exercise.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an obese patientwith an initial body mass index ≧30 kg/m².

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an overweightpatient with an initial body mass index ≧27 kg/m² in the presence of atleast one weight related co-morbid condition.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an overweightpatient with an initial body mass index ≧27 kg/m² in the presence of atleast one weight related co-morbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intolerance,and sleep apnea.

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧30 kg/m².

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧27 kg/m².

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧27 kg/m² in the presence of at leastone weight related co-morbid condition.

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧27 kg/m² in the presence of at leastone weight related co-morbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧25 kg/m².

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧25 kg/m² in the presence of at leastone weight related co-morbid condition.

On aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in an individualwith an initial body mass index ≧25 kg/m² in the presence of at leastone weight related co-morbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of weight management in combination withphentermine.

Crystalline Salts

Polymorphism is the ability of a substance to exist as two or morecrystalline phases that have different arrangements and/or conformationsof the molecules in the crystal lattice. Polymorphs show the sameproperties in the liquid or gaseous state but they may behavedifferently in the solid state.

Besides single-component polymorphs, drugs can also exist as salts andother multicomponent crystalline phases. For example, solvates andhydrates may contain an API host and either solvent or water molecules,respectively, as guests. Analogously, when the guest compound is a solidat room temperature, the resulting form is often called a cocrystal.Salts, solvates, hydrates, and cocrystals may show polymorphism as well.Crystalline phases that share the same API host, but differ with respectto their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in adefinite crystal lattice. Solvates, in which the solvent ofcrystallization is water, are termed hydrates. Because water is aconstituent of the atmosphere, hydrates of drugs may be formed rathereasily.

Recently, polymorph screens of 245 compounds revealed that about 90% ofthem exhibited multiple solid forms. Overall, approximately half thecompounds were polymorphic, often having one to three forms. Aboutone-third of the compounds formed hydrates, and about one-third formedsolvates. Data from cocrystal screens of 64 compounds showed that 60%formed cocrystals other than hydrates or solvates. (G. P. Stahly,Crystal Growth & Design (2007), 7(6), 1007-1026.)

The present invention is directed, inter alia, to crystalline salts of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and hydratesand solvates thereof. The crystalline forms of the salts of the presentinvention can be identified by unique solid state signatures withrespect to, for example, differential scanning calorimetry (DSC), X-raypowder diffraction (PXRD), and other solid state methods. Furthercharacterization with respect to water or solvent content of thecrystalline salts of the present invention can be gauged by any of thefollowing methods for example, thermogravimetric analysis (TGA), DSC andthe like. For DSC, it is known that the temperatures observed willdepend upon sample purity, the rate of temperature change, as well assample preparation technique and the particular instrument employed.Thus, the values reported herein relating to DSC thermograms can vary byabout ±6° C. The values reported herein relating to DSC thermograms canalso vary by about ±20 joules per gram. For PXRD, the relativeintensities of the peaks can vary, depending upon the sample preparationtechnique, the sample mounting procedure and the particular instrumentemployed. Moreover, instrument variation and other factors can oftenaffect the 2θ values. Therefore, the peak assignments of diffractionpatterns can vary by about ±0.2° 2θ. The relative intensities of thereported peaks can also vary. For TGA, the features reported herein canvary by about ±5° C. The TGA features reported herein can also vary byabout ±2% weight change due to, for example, sample variation. Furthercharacterization with respect to hygroscopicity of the crystalline saltcan be gauged by, for example, dynamic moisture sorption (DMS). The DMSfeatures reported herein can vary by about ±5% relative humidity. TheDMS features reported herein can also vary by about ±5% weight change.The deliquescence relative humidity (DRH) measurements by water activitymeter are sensitive to sample quality and quantity. The DRH measurementsreported herein can vary by about ±5% RH.

Compound 1 (1S)-(+)-10-Camsylate Salt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1S)-(+)-10-camsylate salt, Form I (Compound 1 (1 S)-(+)-10-camsylatesalt, Form I). The physical properties of Compound 1(1S)-(+)-10-camsylate salt, Form I are summarized in Table 1 below.

TABLE 1 Compound 1 (1S)-(+)-10-Camsylate Salt, Form I PXRD FIG. 1: Peaksof >20% relative intensity at 9.93, 11.58, 14.90, 15.32, 16.45, 16.88,18.25, 18.57, 20.97, 23.14, and 25.44 °2θ TGA FIG. 2: about 0.2% weightloss up to about 150° C. DSC FIG. 2: extrapolated onset temperature:176° C.; enthalpy of fusion 92 J/g DMS FIG. 3: 0.49% weight increase outto 90% RH

Form I of Compound 1 (1S)-(+)-10-camsylate salt held residual solvent ora small amount of water. The small weight loss by TGA (0.215%) is toosmall to be a stoichiometric solvate; it may be a mixture of anhydroussolvated crystal phases. The melting onset by DSC was 176° C.

Form I of Compound 1 (1S)-(+)-10-camsylate salt was non-hygroscopic byDMS analysis, picking up about 0.49% out to and including the 90% RHhold at 25° C. The DRH was determined to be 99.8% RH by water activitymeasurement of a saturated aqueous solution with excess solid at 25° C.

Certain X-ray powder diffraction peaks for Form I of Compound 1(1S)-(+)-10-camsylate salt are shown in Table 2 below.

TABLE 2 Pos. (°2θ) Rel. Int. (%) 9.93 33.89 11.58 38.89 13.15 2.15 14.088.07 14.43 12.50 14.90 24.42 15.32 25.17 16.45 46.36 16.88 26.94 17.577.59 18.25 100.00 18.57 44.04 19.89 5.97 20.97 41.20 21.36 5.76 21.5610.34 22.54 17.03 23.14 25.60 23.28 16.29 24.58 6.00 24.90 10.60 25.3014.05 25.44 23.97 25.82 8.07 26.41 2.45 26.92 8.25 27.56 8.59 28.18 6.8128.51 3.91 29.06 1.78 29.52 0.89 30.05 3.29 30.86 5.09 31.11 3.09 31.884.87 32.02 3.96 32.75 5.23 33.23 8.73 33.29 8.45 34.01 2.81 34.32 5.8134.79 1.47 35.31 5.87 36.24 2.66 36.93 4.84 37.61 5.57 38.09 6.29 38.761.26 39.20 1.78

One aspect of the present invention is directed to a Compound 1(1S)-(+)-10-camsylate salt having an X-ray powder diffraction patterncomprising a peak, in terms of 2θ, at about 18.25°. In some embodiments,the crystalline form has an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 16.45°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 18.25° and about 16.45°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 18.25° and about18.57°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 18.25°,about 16.45°, and about 18.57°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 18.25°, about 16.45°, about 18.57°, about 20.97°, about11.58°, about 9.93°, and about 16.88°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 18.25°, about 16.45°, about 18.57°,about 20.97°, about 11.58°, about 9.93°, about 16.88°, about 23.14°,about 15.32°, and about 14.90°. One aspect of the present invention isdirected to a Compound 1 (1S)-(+)-10-camsylate salt having an X-raypowder diffraction pattern comprising one or more peaks listed in Table2. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern substantially as shown in FIG. 1, wherein by“substantially” is meant that the reported peaks can vary by about ±0.2°2θ, and also that the relative intensities of the reported peaks canvary.

In some embodiments, the Compound 1 (1S)-(+)-10-camsylate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 160° C. and about190° C. In some embodiments, the Compound 1 (1S)-(+)-10-camsylate salthas a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 176° C. Insome embodiments, the Compound 1 (1S)-(+)-10-camsylate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an associated heat flow of about 92 joules per gram. In someembodiments, the Compound 1 (1S)-(+)-10-camsylate salt has adifferential scanning calorimetry thermogram substantially as shown inFIG. 2, wherein by “substantially” is meant that the reported DSCfeatures can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 (1S)-(+)-10-camsylate salt has athermogravimetric analysis profile substantially as shown in FIG. 2,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 (1S)-(+)-10-camsylate salt has adynamic moisture sorption profile substantially as shown in FIG. 3,wherein by “substantially” is meant that the reported DMS features canvary by about ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 (1S)-(+)-10-camsylate salt can be prepared by anyof the suitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1(1S)-(+)-10-camsylate salt can be prepared as described in Example 1. Insome embodiments, Form I of Compound 1 (1S)-(+)-10-camsylate salt can beprepared by slurrying crystalline Compound 1 (1S)-(+)-10-camsylate saltcontaining one or more crystalline forms other than Form I. In someembodiments, Form I of Compound 1 (1S)-(+)-10-camsylate salt can beprepared by recrystallizing crystalline Compound 1 (1S)-(+)-10-camsylatesalt containing one or more crystalline forms other than Form I.

Compound 1 Hemi-L-Malate Salt

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt, Form I (Compound 1 hemi-L-malate salt, Form I). The physicalproperties of Compound 1 hemi-L-malate salt, Form I are summarized inTable 3 below.

TABLE 3 Compound 1 Hemi-L-Malate Salt, Form I PXRD FIG. 4: Peaks of ≧25%relative intensity at 7.18, 10.84, 11.7932, 15.09, 19.14, 19.36, 20.34,20.45, 21.26, 21.97, and 23.25 °2θ TGA FIG. 5: less than 0.3% weightloss up to about 120° C. DSC FIG. 5: extrapolated onset temperatureabout 156° C.; enthalpy of fusion 106 J/g DMS FIG. 6: deliquescencebetween 80 and 90% RH

Compound 1 hemi-L-malate salt, Form I was crystalline and melted with anonset temperature of 155-156° C. It demonstrated deliquescence between80 and 90% RH by DMS analysis.

Certain X-ray powder diffraction peaks for Form I of Compound 1hemi-L-malate salt are shown in Table 4 below.

TABLE 4 Pos. (°2θ) Rel. Int. (%) 7.18 33.59 9.41 12.07 10.84 100.0011.79 88.54 13.78 3.71 14.34 2.76 15.09 31.06 16.36 4.57 16.77 7.8218.76 21.71 19.14 26.02 19.36 26.41 19.87 11.41 20.34 29.98 20.45 28.5520.94 19.62 21.26 39.19 21.64 20.60 21.97 42.90 23.01 23.35 23.25 26.6623.61 23.48 24.19 18.55 25.16 13.20 25.69 9.53 26.58 6.73 26.92 12.2127.65 7.52 28.20 4.75 28.81 6.71 29.50 3.72 29.88 5.71 30.43 4.91 32.756.12 33.68 3.88 34.02 3.72 35.16 6.57 35.95 4.32 36.85 1.25 37.53 1.9938.11 1.54 39.1250 2.61

One aspect of the present invention is directed to a Compound 1hemi-L-malate salt having an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 10.84°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 11.7932°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 10.84° and about 11.7932°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 10.84° and about21.97°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 10.84°,about 11.7932°, and about 21.97°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 10.84°, about 11.7932°, about 21.97°, about 21.26°,about 7.18°, about 15.09°, and about 20.34°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 10.84°, about 11.7932°, about 21.97°,about 21.26°, about 7.18°, about 15.09°, about 20.34°, about 20.45°,about 23.25°, and about 19.36°. One aspect of the present invention isdirected to a Compound 1 hemi-L-malate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 4. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 4, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 hemi-L-malate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 140° C. and about170° C. In some embodiments, the Compound 1 hemi-L-malate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 156° C. In someembodiments, the Compound 1 hemi-L-malate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anassociated heat flow of about 106 joules per gram. In some embodiments,the Compound 1 hemi-L-malate salt has a thermogravimetric analysisprofile substantially as shown in FIG. 5, wherein by “substantially” ismeant that the reported TGA features can vary by about ±5° C. and byabout ±2% weight change.

In some embodiments, the Compound 1 hemi-L-malate salt has adifferential scanning calorimetry thermogram substantially as shown inFIG. 5, wherein by “substantially” is meant that the reported DSCfeatures can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 hemi-L-malate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 6, wherein by“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 hemi-L-malate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 hemi-L-malate saltcan be prepared as described in Example 2. In some embodiments, Form Iof Compound 1 hemi-L-malate salt can be prepared by slurryingcrystalline Compound 1 hemi-L-malate salt containing one or morecrystalline forms other than Form I. In some embodiments, Form I ofCompound 1 hemi-L-malate salt can be prepared by recrystallizingcrystalline Compound 1 hemi-L-malate salt containing one or morecrystalline forms other than Form I.

Compound 1 L-Glutamate Salt

One aspect of the present invention pertains to a(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt (Compound 1 L-glutamate salt). In some embodiments, the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt is Form I (Compound 1 L-glutamate salt, Form I). The physicalproperties of Form I of Compound 1 L-glutamate salt are summarized inTable 5 below.

TABLE 5 Compound 1 L-Glutamate Salt, Form I PXRD FIG. 7: Peaks of ≧20%relative intensity at 5.79, 16.88, 17.63, 18.06, 18.24, 20.25, 21.27,21.78, 22.46, 23.73, and 25.59 °2θ TGA FIG. 8: about 0.25% weight lossup to about 124° C. DSC FIG. 8: extrapolated onset temperature about187° C.; enthalpy of fusion 288 J/g DMS FIG. 9: non-hygroscopic, about0.1% weight gain out 90% RH

Compound 1 L-glutamate salt, Form I had a melting onset of 187° C. Alarge portion of the salt, a degradant or component, was lost prior tomelting, based on the TGA result. The salt was anhydrous andnon-hygroscopic.

Certain X-ray powder diffraction peaks for Form I of Compound 1L-glutamate salt are shown in Table 6 below.

TABLE 6 Pos. (°2θ) Rel. Int. (%) 5.79 31.50 10.61 8.24 11.59 10.80 12.831.38 15.22 17.13 16.88 24.59 17.63 99.12 18.06 41.01 18.24 29.49 19.075.69 20.25 47.15 21.27 34.93 21.78 80.76 22.46 23.35 22.92 13.91 23.7349.50 25.59 100.00 26.00 19.27 26.98 5.80 27.36 2.03 28.32 13.14 28.942.08 29.2382 7.91 29.5508 2.11 30.2671 13.89 30.6035 4.84 31.20 5.2231.96 2.89 32.61 5.41 32.94 10.36 33.62 1.96 34.31 3.53 34.93 2.03 35.247.29 35.60 11.62 36.66 18.40 37.03 10.33 37.25 8.52 37.54 5.74 38.174.11 38.49 5.75 38.76 4.61 39.10 3.60

One aspect of the present invention is directed to a Compound 1L-glutamate salt having an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 25.59°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 17.63°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 25.59° and about 17.63°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 25.59° and about21.78°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 25.59°,about 17.63°, and about 21.78°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 25.59°, about 17.63°, about 21.78°, about 23.73°, about20.25°, about 18.06°, and about 21.27°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 25.59°, about 17.63°, about 21.78°,about 23.73°, about 20.25°, about 18.06°, about 21.27°, about 5.79°,about 18.24°, and about 16.88°. One aspect of the present invention isdirected to a Compound 1 L-glutamate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 6. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 7, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 L-glutamate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 170° C. and about 200° C.In some embodiments, the Compound 1 L-glutamate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature at about 187° C. In some embodiments, theCompound 1 L-glutamate salt has a differential scanning calorimetrythermogram comprising an endotherm with an associated heat flow of about288 joules per gram. In some embodiments, the Compound 1 L-glutamatesalt has a thermogravimetric analysis profile substantially as shown inFIG. 8, wherein by “substantially” is meant that the reported TGAfeatures can vary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 L-glutamate salt has a differentialscanning calorimetry thermogram substantially as shown in FIG. 8,wherein by “substantially” is meant that the reported DSC features canvary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 L-glutamate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 9. By“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 L-glutamate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 L-glutamate saltcan be prepared as described in Example 3. In some embodiments, Form Iof Compound 1 L-glutamate salt can be prepared by slurrying crystallineCompound 1 L-glutamate salt containing one or more crystalline formsother than Form I. In some embodiments, Form I of Compound 1 L-glutamatesalt can be prepared by recrystallizing crystalline Compound 1L-glutamate salt containing one or more crystalline forms other thanForm I.

Compound 1 L-Aspartate Salt

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt, Form I (Compound 1 L-aspartate salt, Form I). The physicalproperties of Compound 1 L-aspartate salt, Form I are summarized inTable 7 below.

TABLE 7 Compound 1 L-Aspartate Salt, Form I PXRD FIG. 10: Peaks of ≧25%relative intensity at 8.49, 13.40, 15.28, 16.43, 16.55, 19.45, 20.80,21.22, 22.08, 22.38, 23.29, and 29.85 °2θ TGA FIG. 11: 54.9% weight fromabout 140° C. to about 200° C. DSC FIG. 11: extrapolated onsettemperature about 174° C. DMS FIG. 12: hygroscopic at 70% RH anddeliquescent above 70% RH

Form I of Compound 1 L-aspartate salt was an anhydrous crystal phasethat melted at 173.9° C. It displayed back-to-back endothermic eventscorresponding to simultaneous loss of a degradant or a component of thesalt, and melting. The TGA showed a large step transition (weight-loss),thus DSC endothermic events are accompanied by volatilization of someportion of the sample.

DMS showed it to be slightly hygroscopic at 70% RH and deliquescentabove 70% RH, picking up 28% weight during the 80% RH hold, 45% of itsweight in water out to and including the 90% RH hold at 25° C.

Certain X-ray powder diffraction peaks for Form I of Compound 1L-aspartate salt are shown in Table 8 below.

TABLE 8 Pos. (°2θ) Rel. Int. (%) 5.12 1.93 8.49 89.49 12.75 4.03 13.4071.47 14.20 4.37 15.28 68.22 16.43 35.18 16.55 35.20 16.96 6.96 17.495.41 17.98 3.56 19.45 29.32 20.80 64.93 21.22 100.00 21.69 20.38 22.0845.99 22.38 36.19 23.29 45.28 23.56 7.19 24.33 17.79 25.18 6.08 25.567.58 26.33 15.10 26.66 9.03 26.88 21.72 27.71 1.47 28.27 7.21 28.6013.17 29.85 56.07 30.49 24.42 31.14 9.83 31.38 24.01 32.29 2.26 33.0611.70 33.98 4.21 34.23 10.10 34.82 10.62 35.02 8.80 36.40 8.61 36.608.18 37.01 2.54 37.35 3.76 37.67 2.82 38.13 4.28 38.43 7.61 38.74 4.6539.43 3.29

One aspect of the present invention is directed to a Compound 1L-aspartate salt having an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 21.22°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 8.49°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 21.22° and about 8.49°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 21.22° and about13.40°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 21.22°,about 8.49°, and about 13.40°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising peaks, in terms of2θ, at about 21.22°, about 8.49°, about 13.40°, about 15.28°, about29.85°, about 29.85°, and about 22.08°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 21.22°, about 8.49°, about 13.40°, about15.28°, about 29.85°, about 29.85°, about 22.08°, about 23.29°, about22.38°, and about 16.55°. One aspect of the present invention isdirected to a Compound 1 L-aspartate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 8. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 10, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 L-aspartate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 160° C. and about 190° C.In some embodiments, the Compound 1 L-aspartate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature at about 174° C. In some embodiments, theCompound 1 L-aspartate salt has a thermogravimetric analysis profilesubstantially as shown in FIG. 11, wherein by “substantially” is meantthat the reported TGA features can vary by about ±5° C. and by about ±2%weight change.

In some embodiments, the Compound 1 L-aspartate salt has a differentialscanning calorimetry thermogram substantially as shown in FIG. 11,wherein by “substantially” is meant that the reported DSC features canvary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 L-aspartate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 12, wherein by“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 L-aspartate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 L-aspartate saltcan be prepared as described in Example 4. In some embodiments, Form Iof Compound 1 L-aspartate salt can be prepared by slurrying crystallineCompound 1 L-aspartate salt containing one or more crystalline formsother than Form I. In some embodiments, Form I of Compound 1 L-aspartatesalt can be prepared by recrystallizing crystalline Compound 1L-aspartate salt containing one or more crystalline forms other thanForm I.

Compound 1 Hemimucate Salt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate,Form I (Compound 1 hemimucate salt, Form I). The physical properties ofCompound 1 hemimucate salt, Form I are summarized in Table 9 below.

TABLE 9 Compound 1 Hemimucate Salt, Form I PXRD FIG. 13: Peaks of >4%relative intensity at 5.06, 10.06, 14.57, 15.90, 18.60, 18.89, 20.92,21.46, 21.63, 22.74, 23.0980, and 25.61 °2θ TGA FIG. 14: 56% weight lossfrom about 175° C. to about 215° C. DSC FIG. 14: extrapolated onsettemperature: 208° C.; enthalpy of fusion 358 J/g DMS FIG. 15: 0.255%weight increase out to 90% RH

Form I of Compound 1 hemimucate salt exhibited a melting onset at 208°C. The large heat of fusion (357.5 J/g shown in FIG. 14) was due inlarge part to vaporization of more than half of the sample, indicatingthe salt melts with degradation.

Compound 1 hemimucate salt was essentially non-hygroscopic, picking uponly 0.26% weight in water out to and including the 90% RH hold at 25°C.

Certain X-ray powder diffraction peaks for Form I of Compound 1hemimucate salt are shown in Table 10 below.

TABLE 10 Pos. (°2θ) Rel. Int. (%) 5.06 100.00 10.06 9.14 10.62 0.2611.67 1.51 12.08 0.05 14.08 1.50 14.57 11.53 15.07 0.53 15.90 6.75 18.011.55 18.60 28.58 18.89 8.11 20.12 0.24 20.92 13.14 21.46 4.96 21.63 8.2522.29 2.45 22.74 4.12 23.10 4.24 23.86 0.41 24.27 3.09 25.22 3.81 25.614.48 26.44 1.12 26.85 1.86 27.37 1.54 27.88 1.72 28.29 0.75 28.92 3.1129.28 1.36 30.37 2.29 31.44 1.06 31.60 1.04 32.29 0.96 32.64 0.49 33.301.90 34.00 0.39 34.40 0.59 35.18 0.40 35.42 0.52 36.17 0.39 36.78 0.2137.65 1.54 38.12 1.29 38.51 0.37

One aspect of the present invention is directed to a Compound 1hemimucate salt having an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 5.06°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 18.60°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 5.06° and about 18.60°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 5.06° and about20.92°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 5.06°,about 18.60°, and about 20.92°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 5.06°, about 18.60°, about 20.92°, about 14.57°, about10.06°, about 21.63°, and about 18.89°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 5.06°, about 18.60°, about 20.92°, about14.57°, about 10.06°, about 21.63°, about 18.89°, about 15.90°, about21.46°, and about 25.61°. One aspect of the present invention isdirected to a Compound 1 hemimucate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 10. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 13, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 hemimucate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 190° C. and about 220° C.In some embodiments, the Compound 1 hemimucate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature at about 208° C. In some embodiments, theCompound 1 hemimucate salt has a differential scanning calorimetrythermogram comprising an endotherm with an associated heat flow of about358 joules per gram. In some embodiments, the Compound 1 hemimucate salthas a differential scanning calorimetry thermogram substantially asshown in FIG. 14, wherein by “substantially” is meant that the reportedDSC features can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 hemimucate salt has athermogravimetric analysis profile substantially as shown in FIG. 14,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 hemimucate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 15, wherein by“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 hemimucate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 hemimucate salt canbe prepared as described in Example 5. In some embodiments, Form I ofCompound 1 hemimucate salt can be prepared by slurrying crystallineCompound 1 hemimucate salt containing one or more crystalline formsother than Form I. In some embodiments, Form I of Compound 1 hemimucatesalt can be prepared by recrystallizing crystalline Compound 1hemimucate salt containing one or more crystalline forms other than FormI.

Compound 1 Glucuronate Salt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronate,Form I (Compound 1 glucuronate salt, Form I). The physical properties ofCompound 1 glucuronate salt, Form I are summarized in Table 11 below.

TABLE 11 Compound 1 Glucuronate Salt, Form I PXRD FIG. 16: Peaks of 10>%relative intensity at 5.59, 12.54, 16.46, 17.41, 18.40, 20.48, 20.69,22.12, 26.66, 27.53, 27.85, and 29.57 °2θ TGA FIG. 17: about 20% weightloss from about 150° C. to about 165° C. DSC FIG. 17: extrapolated onsettemperature: 164° C.; enthalpy of fusion 124 J/g DMS FIG. 18: 0.16%weight increase out to 90% RH

Compound 1 glucuronate salt was an anhydrous crystalline material withmelting onset of ˜164° C. Based on rapid weight loss of about 20%starting just prior to the melting onset, this salt melted withdegradation. It was non-hygroscopic by DMS picking up about 0.16% out toand including the 90% RH hold at 25° C.

Certain X-ray powder diffraction peaks for Form I of Compound 1glucuronate salt are shown in Table 12 below.

TABLE 12 Pos. (°2θ) Rel. Int. (%) 5.59 71.04 11.10 1.23 12.54 55.7713.43 2.10 14.79 5.71 16.46 100.00 17.41 42.46 18.09 7.55 18.40 58.2919.10 1.99 20.48 55.27 20.69 30.98 22.12 22.45 22.90 8.02 23.98 3.4624.20 4.29 24.68 9.76 25.13 6.41 25.94 2.74 26.66 10.40 27.26 5.26 27.5310.09 27.85 14.59 28.19 7.69 28.64 2.99 29.39 9.66 29.57 12.34 30.475.19 31.42 9.83 31.98 5.74 32.84 6.85 33.55 5.41 34.78 3.60 35.28 4.1235.68 4.57 37.18 5.03 37.42 6.79 38.44 4.53 38.68 4.38 39.21 5.43 39.584.06

One aspect of the present invention is directed to a Compound 1glucuronate salt having an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 16.46°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 5.59°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 16.46° and about 5.59°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 16.46° and about18.40°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 16.46°,about 5.59°, and about 18.40°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising peaks, in terms of2θ, at about 16.46°, about 5.59°, about 18.40°, about 12.54°, about20.48°, about 17.41°, and about 20.69°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 16.46°, about 5.59°, about 18.40°, about12.54°, about 20.48°, about 17.41°, about 20.69°, about 22.12°, about27.85°, and about 29.57°. One aspect of the present invention isdirected to a Compound 1 glucuronate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 12. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 16, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 glucuronate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 150° C. and about 180° C.In some embodiments, the Compound 1 glucuronate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature at about 164° C. In some embodiments, theCompound 1 glucuronate salt has a differential scanning calorimetrythermogram comprising an endotherm with an associated heat flow of about124 joules per gram. In some embodiments, the Compound 1 glucuronatesalt has a differential scanning calorimetry thermogram substantially asshown in FIG. 17, wherein by “substantially” is meant that the reportedDSC features can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 glucuronate salt has athermogravimetric analysis profile substantially as shown in FIG. 17,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 glucuronate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 18, wherein by“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 glucuronate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 glucuronate saltcan be prepared as described in Example 6. In some embodiments, Form Iof Compound 1 glucuronate salt can be prepared by slurrying crystallineCompound 1 glucuronate salt containing one or more crystalline formsother than Form I. In some embodiments, Form I of Compound 1 glucuronatesalt can be prepared by recrystallizing crystalline Compound 1glucuronate salt containing one or more crystalline forms other thanForm I.

Compound 1 Pyrogluconate Salt.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyrogluconate,Form I (Compound 1 pyrogluconate salt, Form I). The physical propertiesof Compound 1 pyrogluconate salt, Form I are summarized in Table 13below.

TABLE 13 Compound 1 Pyrogluconate Salt, Form I PXRD FIG. 19: Peaksof >12% relative intensity at 6.78, 14.69, 16.50, 16.95, 17.61, 18.40,18.80, 20.66, 22.72, 22.99, 24.47, and 27.84 °2θ TGA FIG. 20: Nosignificant weight loss prior to melting DSC FIG. 20: extrapolated onsettemperature: 139° C.; enthalpy of fusion 70.8 J/g DMS FIG. 21: 17-24%weight increase at 70% RH, about 50% weight increase at 90% RH

Form I of Compound 1 pyrogluconate salt was a crystalline solid with asmall broad endotherm prior to a melting endotherm with an onset at 139°C. and heat of fusion of 70.8 J/g. Prior to the melting onset there wasminimal weight loss by TGA and upon melting there was a gradual andcomplete weight loss, indicating the isolated crystal phase was not asolvate.

Compound 1 pyroglutamate salt, Form I was hygroscopic aboveapproximately 50% RH, picking up during the adsorption cycle nearly 17%water at 70% RH, nearly 50% water out to and including the 90% RH holdat 25° C. and still gaining weight after 2 h at 90% RH. The samplesubsequently retained much of the water, even down to 10% RH. The sampleafter removal from the dynamic moisture-sorption analyzer was a stickyoil, so no further analysis was performed.

Certain X-ray powder diffraction peaks for Form I of Compound 1pyrogluconate salt are shown in Table 14 below.

TABLE 14 Pos. (°2θ) Rel. Int. (%) 6.78 100.00 8.23 1.01 8.81 0.12 9.811.29 11.46 10.49 13.52 8.13 14.69 12.51 14.93 0.29 15.64 0.69 16.5013.75 16.95 29.48 17.61 19.64 18.40 28.95 18.80 42.64 19.34 9.09 19.644.51 19.74 4.37 20.31 6.19 20.66 25.68 21.43 9.44 22.20 2.03 22.72 21.9422.99 15.93 24.47 26.51 24.66 6.06 25.11 4.29 25.65 1.49 25.95 2.4426.31 0.97 26.77 9.30 27.15 3.37 27.84 15.61 27.95 9.89 28.79 1.85 29.3910.02 29.66 2.60 30.20 1.19 30.72 5.02 31.41 4.47 32.37 1.31 32.47 1.1832.88 1.48 33.53 4.21 33.93 1.51 34.12 3.03 34.21 3.29 34.77 0.82 35.080.22 35.57 3.35 36.30 0.45 36.55 1.29 36.89 1.92 37.49 2.67 38.05 1.5338.57 0.08 39.05 0.39 39.25 0.16 39.78 1.97

One aspect of the present invention is directed to a Compound 1pyrogluconate salt having an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 6.78°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 18.80°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 6.78° and about 18.80°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 6.78° and about16.95°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 6.78°,about 18.80°, and about 16.95°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 6.78°, about 18.80°, about 16.95°, about 18.40°, about24.47°, about 20.66°, and about 22.72°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 6.78°, about 18.80°, about 16.95°, about18.40°, about 24.47°, about 20.66°, about 22.72°, about 17.61°, about22.99°, and about 27.84°. One aspect of the present invention isdirected to a Compound 1 pyrogluconate salt having an X-ray powderdiffraction pattern comprising one or more peaks listed in Table 14. Insome embodiments, the crystalline form has an X-ray powder diffractionpattern substantially as shown in FIG. 19, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2° 2θ, and also thatthe relative intensities of the reported peaks can vary.

In some embodiments, the Compound 1 pyrogluconate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 120° C. and about150° C. In some embodiments, the Compound 1 pyrogluconate salt has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 139° C. In someembodiments, the Compound 1 pyrogluconate salt has a differentialscanning calorimetry thermogram comprising an endotherm with anassociated heat flow of about 73 joules per gram. In some embodiments,the Compound 1 pyrogluconate salt has a differential scanningcalorimetry thermogram substantially as shown in FIG. 20, wherein by“substantially” is meant that the reported DSC features can vary byabout ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 pyrogluconate salt has athermogravimetric analysis profile substantially as shown in FIG. 20,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 pyrogluconate salt has a dynamicmoisture sorption profile substantially as shown in FIG. 21, wherein by“substantially” is meant that the reported DMS features can vary byabout ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 pyrogluconate salt can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 pyrogluconate saltcan be prepared as described in Example 7. In some embodiments, Form Iof Compound 1 pyrogluconate salt can be prepared by slurryingcrystalline Compound 1 pyrogluconate salt containing one or morecrystalline forms other than Form I. In some embodiments, Form I ofCompound 1 pyrogluconate salt can be prepared by recrystallizingcrystalline Compound 1 pyrogluconate salt containing one or morecrystalline forms other than Form I.

Compound 1 Di-Camphorate Salt Solvate.

One aspect of the present invention pertains to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate, Form I (Compound 1 di-camphorate salt solvate, Form I).The physical properties of Compound 1 di-camphorate salt solvate, Form Iare summarized in Table 15 below.

TABLE 15 Compound 1 Di-camphorate Salt Solvate, Form I PXRD FIG. 22:Peaks of >25% relative intensity at 7.39, 7.80, 8.91, 13.01, 15.01,15.20, 15.58, 15.70, 17.83, 23.00, and 23.25 °2θ TGA FIG. 23: 4.135%weight loss up to about 110° C. DSC FIG. 23: extrapolated onsettemperature: 90° C.; enthalpy of fusion 55 J/g DMS FIG. 24: 1.8% weightincrease out to 90% RH

Form I of Compound 1 di-camphorate salt solvate showed a broad meltingonset at approximately 90° C. and an enthalpy of fusion of 55 J/g byDSC. By TGA the sample lost approximately 4% of its weight duringmelting/desolvation and continued to lose weight after the melt.

During DMS analysis of Compound 1 di-camphorate salt solvate the samplegained up to 1.8% weight in water out to and including the 90% RH holdat 25° C. Hysteresis was evident on the desorption isotherm. The samplelost over 1.2% weight on the desorption phase at 25° C. and 10% RH,which had not been removed during the drying step at 40° C. and ˜1% RH.After DMS analysis the sample remained a white solid, and the PXRDpattern of this material was consistent with the original materialindicating that the crystalline phase did not change.

Certain X-ray powder diffraction peaks for Form I of Compound 1di-camphorate salt solvate are shown in Table 16 below.

TABLE 16 Pos. (°2θ) Rel. Int. (%) 7.39 35.15 7.80 43.69 8.91 27.48 10.4614.91 10.86 6.49 12.56 13.13 13.01 34.99 14.61 21.92 15.01 29.30 15.2035.92 15.58 66.15 15.70 100.00 17.83 52.03 18.60 10.25 19.69 16.79 20.229.67 20.95 23.04 21.40 9.52 21.75 13.25 22.21 5.09 22.72 10.43 23.0031.07 23.25 26.41 24.37 5.27 24.70 5.87 25.78 14.42 26.73 4.39 27.734.76 28.52 3.94 30.00 3.04 30.43 3.17 32.71 2.08 35.07 2.00 37.30 3.13

One aspect of the present invention is directed to a Compound 1di-camphorate salt solvate having an X-ray powder diffraction patterncomprising a peak, in terms of 2θ, at about 15.70°. In some embodiments,the crystalline form has an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 15.58°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 15.70° and about 15.58°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 15.70° and about17.83°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 15.70°,about 15.58°, and about 17.83°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 15.70°, about 15.58°, about 17.83°, about 7.80°, about15.20°, about 7.39°, and about 13.01°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 15.70°, about 15.58°, about 17.83°,about 7.80°, about 15.20°, about 7.39°, about 13.01°, about 23.00°,about 15.01°, and about 8.91°. One aspect of the present invention isdirected to a Compound 1 di-camphorate salt solvate having an X-raypowder diffraction pattern comprising one or more peaks listed in Table16. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern substantially as shown in FIG. 22, wherein by“substantially” is meant that the reported peaks can vary by about ±0.2°2θ, and also that the relative intensities of the reported peaks canvary.

In some embodiments, the Compound 1 di-camphorate salt solvate has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 75° C. and about105° C. In some embodiments, the Compound 1 di-camphorate salt solvatehas a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 90° C. In someembodiments, the Compound 1 di-camphorate salt solvate has adifferential scanning calorimetry thermogram comprising an endothermwith an associated heat flow of about 55 joules per gram. In someembodiments, the Compound 1 di-camphorate salt solvate has adifferential scanning calorimetry thermogram substantially as shown inFIG. 23, wherein by “substantially” is meant that the reported DSCfeatures can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the Compound 1 di-camphorate salt solvate has athermogravimetric analysis profile substantially as shown in FIG. 23,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C. and by about ±2% weight change.

In some embodiments, the Compound 1 di-camphorate salt solvate has adynamic moisture sorption profile substantially as shown in FIG. 24,wherein by “substantially” is meant that the reported DMS features canvary by about ±5% relative humidity and by about ±5% weight change.

Form I of Compound 1 di-camphorate salt solvate can be prepared by anyof the suitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form I of Compound 1 di-camphorate saltsolvate can be prepared as described in Example 8. In some embodiments,Form I of Compound 1 di-camphorate salt solvate can be prepared byslurrying crystalline Compound 1 di-camphorate salt solvate containingone or more crystalline forms other than Form I. In some embodiments,Form I of Compound 1 di-camphorate salt solvate can be prepared byrecrystallizing crystalline Compound 1 di-camphorate salt solvatecontaining one or more crystalline forms other than Form I.

One aspect of the present invention pertains to processes for preparinga pharmaceutical composition comprising admixing a crystalline salt ofthe present invention, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to processes for preparinga bulk pharmaceutical composition comprising admixing a crystalline saltof the present invention, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a crystalline salt of the presentinvention.

One aspect of the present invention pertains to the use of crystallinesalts of the present invention, in the manufacture of a medicament forweight management in an individual.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of treatment of the human oranimal body by therapy.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight loss.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of maintenance of weight loss.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of decreasing food consumption.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of increasing meal-relatedsatiety.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of reducing pre-meal hunger.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of reducing intra-meal foodintake.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management furthercomprising a reduced-calorie diet.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management furthercomprising a program of regular exercise.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management furthercomprising a reduced-calorie diet and a program of regular exercise.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in an obesepatient with an initial body mass index ≧30 kg/m².

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related co-morbid condition. One aspectof the present invention pertains to crystalline salts of the presentinvention, for use in a method of weight management in an overweightpatient with an initial body mass index ≧27 kg/m² in the presence of atleast one weight related co-morbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intolerance,and sleep apnea.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧30 kg/m².

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧27 kg/m².

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related co-morbid condition.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related co-morbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intolerance,and sleep apnea.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧25 kg/m².

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧25 kg/m² in the presence ofat least one weight related co-morbid condition.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management in anindividual with an initial body mass index ≧25 kg/m² in the presence ofat least one weight related co-morbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intolerance,and sleep apnea.

One aspect of the present invention pertains to crystalline salts of thepresent invention, for use in a method of weight management incombination with phentermine.

Optical Resolution

Despite the large number of elaborate enantioselective syntheses for thepreparation of a single enantiomer to achieve industrial and scientificgoals, the separation and purification of enantiomers (components ofracemic compounds) is also necessary.

Methods for resolving optical isomers include, without limitation,spontaneous resolution, induced crystallization, resolution by formationof diastereoisomers, resolution by formation of non-covalentdiastereoisomers, resolution by diastereoisomeric salt formation,resolution by diastereoisomeric complex formation, half equivalentmethods of resolution, separation by crystallization, separation bydistillation, separation by supercritical fluid extraction, resolutionwith mixtures of resolving agents, resolution with a derivative of thetarget compound, enantioselective chromatography, resolution byformation of covalent diastereoisomers, resolution by substrateselective reaction, kinetic resolution without enzymes, kineticresolution by enzyme catalysis, resolution by hydrolytic and redoxenzymes, kinetic and thermodynamic control, resolutions combined withsecond-order asymmetric transformations, and enrichment of partiallyresolved mixtures (Fogassy et al. Optical resolution methods. Organic &Biomolecular Chemistry, (2006), 4(16), 3011-3030).

Resolution by diastereoisomeric salt formation is a popular method forthe resolution of bases. For example, dibenzoyl tartaric acid (DBTA) anddi-p-toluoyl tartaric acid (DPTA) are often used to separate chiralbases (Kozma et al., Chirality, 1999, 11, 373). An intermediate of thepotent anticancer agent flavopyridol was resolved with (R,R)-DBTA (Kimet al. J. Med. Chem., 2000, 43, 4126). cis-1-Amino-2-indanol, anintermediate for indinavir, was resolved with (S)-2-phenylpropionic acid(Sakurai and Sakai, Tetrahedron: Asymmetry, 2003, 14, 411),3-methylamino-1-(2-thienyl)propan-1-ol, an intermediate for duloxetine,was resolved with (S)-mandelic acid (Sakurai et al., Tetrahedron:Asymmetry, 2003, 14, 3713). Optimum conditions for the resolution ofN-methylamphetamine with DPTA (molar ratio, solvent, etc.) wereelaborated (Kozma et al., Chirality, 1999, 11, 373). A similarinvestigation involving N-acetyl-phenylalanine as the resolving agentfor a series of benzodiazepines was recently reported (Burnouf et al.,J. Med. Chem., 2000, 43, 4850). Camphorsulfonic acid was the resolvingagent for a metabolite[1-(3-hydroxy-4-methylphenyl)-2-methyl-3-(1-piperidyl)-propanone] oftolperisone (Bálint et al., Tetrahedron: Asymmetry, 2000, 11, 1323).Tolperisone enantiomers show different biological profiles: while the Renantiomer is a bronchodilator, the S enantiomer is a central musclerelaxant. (1R)-(+)-3-bromocamphor-8-sulfonic acid [(R)-BRCS] is also anefficient resolving agent e.g. for a tetrahydroquinoline intermediate ofthe antibacterial agent flumequine (Bálint et al., Tetrahedron:Asymmetry, 1999, 10, 1079). Resolution of β,γ-unsaturated amines with(S)-2,3-isopropylideneglycerol hemiphthalate is remarkable in that thechiral center of the resolving agent is separated by six bonds from thecarboxyl group (Pallavicini et al., Tetrahedron: Asymmetry, 2000, 11,4017).

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine can beprepared via fractional crystallization resolution of thehemi-L-tartrate salt of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Example 5).Lorcaserin, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, can be prepared by converting(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemi-L-tartrate salt to the free base and then treating with HCl.

In view of the growing demand for compounds useful in the treatment ofdisorders related to the 5-HT_(2C) receptor, new salt forms of racemic8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, withoptically active counterions are needed as intermediates in thepreparation of the corresponding hydrochloride salt. Salt forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with opticallyactive counterions are also useful for directly preparing pharmaceuticalcompositions for the treatment of weight loss. In such compositions theAPI is a salt form of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with anoptically active counterion. Salt forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with opticallyactive counterions can be prepared by treating Compound 1 with opticallyactive acids, or by resolving salt forms of racemic8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with opticallyactive counterions into their diastereoisomers using techniqueswell-known to one of ordinary skill in the art.

Hydrates and Solvates

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates, and hydrates” or the phrase “pharmaceuticallyacceptable salt, solvate, or hydrate” is used when referring tocompounds described herein, it embraces pharmaceutically acceptablesolvates and/or hydrates of the compounds, pharmaceutically acceptablesalts of the compounds, as well as pharmaceutically acceptable solvatesand/or hydrates of pharmaceutically acceptable salts of the compounds.It is also understood that when the phrase “pharmaceutically acceptablesolvates and hydrates” or the phrase “pharmaceutically acceptablesolvate or hydrate” is used when referring to compounds described hereinthat are salts, it embraces pharmaceutically acceptable solvates and/orhydrates of such salts.

It will be apparent to those skilled in the art that the dosage formsdescribed herein may comprise, as the active component, either a saltsor crystalline form thereof as described herein, or a solvate or hydratethereof. Moreover, various hydrates and solvates of the salts orcrystalline form thereof described herein will find use as intermediatesin the manufacture of pharmaceutical compositions. Typical proceduresfor making and identifying suitable hydrates and solvates, outside thosementioned herein, are well known to those in the art; see for example,pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York,1999.

Accordingly, one aspect of the present invention pertains to methods ofadministering hydrates and solvates of salts or crystalline formsthereof described herein and/or their pharmaceutically acceptable salts,that can be isolated and characterized by methods known in the art, suchas, thermogravimetric analysis (TGA), TGA-mass spectroscopy,TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fishertitration, high resolution X-ray diffraction, and the like. There areseveral commercial entities that provide quick and efficient servicesfor identifying solvates and hydrates on a routine basis. Examplecompanies offering these services include Wilmington PharmaTech(Wilmington, Del.), Avantium Technologies (Amsterdam) and Aptuit(Greenwich, Conn.).

Isotopes

The present disclosure includes all isotopes of atoms occurring in thepresent salts and crystalline forms thereof. Isotopes include thoseatoms having the same atomic number but different mass numbers. Oneaspect of the present invention includes every combination of one ormore atoms in the present salts and crystalline forms thereof that isreplaced with an atom having the same atomic number but a different massnumber. One such example is the replacement of an atom that is the mostnaturally abundant isotope, such as ¹H or ¹²C, found in one the presentsalts and crystalline forms thereof, with a different atom that is notthe most naturally abundant isotope, such as ²H or ³H (replacing ¹H), or¹¹C, ¹³C, or ¹⁴C (replacing ¹²C). A salt wherein such a replacement hastaken place is commonly referred to as being isotopically-labeled.Isotopic-labeling of the present salts and crystalline forms thereof canbe accomplished using any one of a variety of different syntheticmethods know to those of ordinary skill in the art and they are readilycredited with understanding the synthetic methods and available reagentsneeded to conduct such isotopic-labeling. By way of general example, andwithout limitation, isotopes of hydrogen include ²H (deuterium) and ³H(tritium). Isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C. Isotopes ofnitrogen include ¹³N and ¹⁵N. Isotopes of oxygen include ¹⁵O, ¹⁷O, and¹⁸C. An isotope of fluorine includes ¹⁸F. An isotope of sulfur includes³⁵S. An isotope of chlorine includes ³⁶Cl. Isotopes of bromine include⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br. Isotopes of iodine include ¹²³I, ¹²⁴I, ¹²⁵I,and ¹³¹I. Another aspect of the present invention includes compositions,such as, those prepared during synthesis, preformulation, and the like,and pharmaceutical compositions, such as, those prepared with the intentof using in a mammal for the treatment of one or more of the disordersdescribed herein, comprising one or more of the present salts andcrystalline forms thereof, wherein the naturally occurring distributionof the isotopes in the composition is perturbed. Another aspect of thepresent invention includes compositions and pharmaceutical compositionscomprising salts and crystalline forms thereof as described hereinwherein the salt is enriched at one or more positions with an isotopeother than the most naturally abundant isotope. Methods are readilyavailable to measure such isotope perturbations or enrichments, such as,mass spectrometry, and for isotopes that are radio-isotopes additionalmethods are available, such as, radio-detectors used in connection withHPLC or GC.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more salts according to any of the saltembodiments disclosed herein and one or more pharmaceutically acceptablecarriers. Some embodiments pertain to pharmaceutical compositionscomprising a salt according to any of the salt embodiments disclosedherein and a pharmaceutically acceptable carrier. Some embodimentspertain to pharmaceutical compositions comprising any subcombination ofsalts according to any of the salt embodiments disclosed herein.

Another aspect of the present invention pertains to methods of producingpharmaceutical compositions comprising admixing one or more saltsaccording to any of the salt embodiments disclosed herein and one ormore pharmaceutically acceptable carriers. Some embodiments pertain to amethod of producing a pharmaceutical composition comprising admixing asalt according to any of the salt embodiments disclosed herein and apharmaceutically acceptable carrier. Some embodiments pertain to amethods of producing pharmaceutical compositions comprising admixing anysubcombination of salts according to any of the salt embodimentsdisclosed herein and a pharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active salt(s) with liquids or finely divided solidcarriers, or both, in the required proportions and then, if necessary,forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the salt of the invention in a suitable liquid vehicle andfilter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

The salts of the present invention can be formulated into pharmaceuticalcompositions and bulk pharmaceutical compositions suitable for themanufacture of dosage forms using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, asalt of the invention may, in an alternative use, be administered as araw or pure chemical, it is preferable however to present the salt oractive ingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The salts of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Salts of the present invention or a solvate, hydrate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2C)-receptormodulators. The term “active ingredient” as defined in the context of a“pharmaceutical composition” and is intended to mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the salts of the present invention can vary withinwide limits and as is customary and is known to the physician, it is tobe tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the salt employed or onwhether an acute or chronic disease state is treated or prophylaxisconducted or on whether further active compounds are administered inaddition to the salts of the present invention. Representative doses ofthe present invention include, but are not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular salt employed,whether a drug delivery system is utilized, on whether an acute orchronic disease state is being treated or prophylaxis conducted or onwhether further active compounds are administered in addition to thesalts of the present invention and as part of a drug combination. Thedosage regimen for treating a disease condition with the salts and/orcompositions of this invention is selected in accordance with a varietyfactors as cited above. Thus, the actual dosage regimen employed mayvary widely and therefore may deviate from a preferred dosage regimenand one skilled in the art will recognize that dosage and dosage regimenoutside these typical ranges can be tested and, where appropriate, maybe used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The salts of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a salt of the invention or a solvate or hydrateof a salt of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive salt. A representative amount in a powder or tablet may containfrom 0.5 to about 90 percent of the active salt; however, an artisanwould know when amounts outside of this range are necessary. Suitablecarriers for powders and tablets are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter and the like. The term “preparation” isintended to include the formulation of the active salt withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the salts according to theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the salts of the presentinvention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thesalts of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the salts of thepresent invention in water, water/alcohol mixtures or suitable salinesolutions can be employed using customary additives, for example benzylalcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the salt will generally have a smallparticle size for example of the order of 10 microns or less. Such aparticle size may be obtained by means known in the art, for example bymicronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the salt in a suitable powderbase such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one salt according to any of the salt embodimentsdisclosed herein, together with at least one known pharmaceutical agentas described herein and a pharmaceutically acceptable carrier.

It is noted that when the salts of the present invention are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as5-HT_(2C)-receptor modulators, for the treatment of a5-HT_(2C)-receptor-associated disease or disorders in companionshipanimals (e.g., cats, dogs, etc.) and in livestock animals (e.g., cows,chickens, fish, etc.). Those of ordinary skill in the art are readilycredited with understanding the utility of such salts in such settings.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a pharmaceutical composition of thepresent invention.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightloss.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method ofmaintenance of weight loss.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of decreasingfood consumption.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of increasingmeal-related satiety.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of reducingpre-meal hunger.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of reducingintra-meal food intake.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a reduced-calorie diet.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a program of regular exercise.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a reduced-calorie diet and a program ofregular exercise.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an obese patient with an initial body mass index ≧30kg/m².

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an overweight patient with an initial body mass index ≧27kg/m² in the presence of at least one weight related co-morbidcondition.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an overweight patient with an initial body mass index ≧27kg/m² in the presence of at least one weight related co-morbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance, and sleep apnea.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧30 kg/m².

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m².

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related co-morbid condition.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related co-morbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m².

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m² inthe presence of at least one weight related co-morbid condition.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m² inthe presence of at least one weight related co-morbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

One aspect of the present invention pertains to pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in combination with phentermine.

Indications

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas, but not limited to, type II diabetes, hypertension, stroke, certainforms of cancers and gallbladder disease.

Obesity has become a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in the numberof obese people is due largely to the increasing preference for high fatcontent foods but also, and this can be a more important factor, thedecrease in activity in most people's lives. In spite of the growingawareness of the health concerns linked to obesity the percentage ofindividuals that are overweight or obese continues to increase. The mostsignificant concern, from a public health perspective, is that childrenwho are overweight grow up to be overweight or obese adults, andaccordingly are at greater risk for major health problems. Therefore, itappears that the number of individuals that are overweight or obese willcontinue to increase.

Whether someone is classified as overweight or obese is generallydetermined on the basis of his or her body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units for BMI are kg/m². BMI is more highly correlated with body fatthan any other indicator of height and weight. A person is consideredoverweight when they have a BMI in the range of 25-30 kg/m², whereas aperson with a BMI over 30 kg/m² is classified as obese. Obesity isfurther divided into three classes: Class I (BMI of about 30 to about34.9 kg/m²), Class II (BMI of about 35 to 39.9 kg/m²) and Class III(about 40 kg/m² or greater); see Table below for completeclassifications.

Classification Of Weight By Body Mass Index (BMI) BMI CLASSIFICATION<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9Obesity (Class I) 35.0-39.9 Obesity (Class II) >40   Extreme Obesity(Class III)

As the BMI increases for an individual there is an increased risk ofmorbidity and mortality relative to an individual with normal BMI.Accordingly, overweight and obese individuals (BMI of about 25 kg/m² andabove) are at increased risk for physical ailments such as, but notlimited to, high blood pressure, cardiovascular disease (particularlyhypertension), high blood cholesterol, dyslipidemia, type II(non-insulin dependent) diabetes, insulin resistance, glucoseintolerance, hyperinsulinemia, coronary heart disease, angina pectoris,congestive heart failure, stroke, gallstones, cholescystitis andcholelithiasis, gout, osteoarthritis, obstructive sleep apnea andrespiratory problems, some types of cancer (such as endometrial, breast,prostate, and colon), complications of pregnancy, poor femalereproductive health (such as menstrual irregularities, infertility,irregular ovulation), diseases of reproduction (such as sexualdysfunction, both male and female, including male erectile dysfunction),bladder control problems (such as stress incontinence), uric acidnephrolithiasis, psychological disorders (such as depression, eatingdisorders, distorted body image, and low self esteem). Research hasshown that even a modest reduction in body weight can correspond to asignificant reduction in the risk of developing other ailments, such as,but not limited to, coronary heart disease.

As mentioned above, obesity increases the risk of developingcardiovascular diseases. Coronary insufficiency, atheromatous disease,and cardiac insufficiency are at the forefront of the cardiovascularcomplications induced by obesity. The incidence of coronary diseases isdoubled in subjects less than 50 years of age who are 30% overweight.The diabetes patient faces a 30% reduced lifespan. After age 45, peoplewith diabetes are about three times more likely than people withoutdiabetes to have significant heart disease and up to five times morelikely to have a stroke. These findings emphasize the inter-relationsbetween risks factors for type 2 diabetes and coronary heart disease andthe potential value of an integrated approach to the prevention of theseconditions based on the prevention of obesity [Perry, I. J., et al. BMJ310, 560-564 (1995)]. It is estimated that if the entire population hadan ideal weight, the risk of coronary insufficiency would decrease by25% and the risk of cardiac insufficiency and of cerebral vascularaccidents by 35%.

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina andincreases the risk of cataracts and glaucoma. Finally, diabetes isassociated with nerve damage, especially in the legs and feet, whichinterferes with the ability to sense pain and contributes to seriousinfections. Taken together, diabetes complications are one of thenation's leading causes of death.

The first line of treatment for individuals that are overweight or obeseis to offer diet and life style advice, such as, reducing the fatcontent of their diet and increasing their physical activity. Howevermany patients find these difficult to maintain and need additional helpfrom drug therapy to sustain results from these efforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity owing to a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of the patient populationled to its withdrawal by the FDA in 1998.

The 5-HT_(2C) receptor is recognized as a well-accepted receptor targetfor the treatment of obesity, psychiatric, and other disorders. See, forexample, Halford et al., Serotonergic Drugs Effects on AppetiteExpression and Use for the Treatment of Obesity, Drugs 2007; 67 (1):27-55; Naughton et al., A Review Of The Role Of Serotonin Receptors InPsychiatric Disorders. Human Psychopharmacology (2000), 15(6), 397-415.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(lorcaserin hydrochloride) is an agonist of the 5-HT_(2C) receptor andshows effectiveness at reducing obesity in animal models and humans. Ina phase 3 human clinical trial evaluating the safety and efficacy oflorcaserin for weight management, statistical significance (p<0.0001)was achieved on all three of the hierarchically ordered co-primaryendpoints for patients treated with lorcaserin versus placebo. Treatmentwith lorcaserin was generally very well tolerated. An assessment ofechocardiograms indicated no apparent drug-related effect on thedevelopment of US Food and Drug Administration (FDA)-definedvalvulopathy over the two-year treatment period. The hierarchicallyordered endpoints were the proportion of patients achieving 5% orgreater weight loss after 12 months, the difference in mean weight losscompared to placebo after 12 months, and the proportion of patientsachieving 10% or greater weight loss after 12 months. Compared toplacebo, using an intent-to-treat last observation carried forward(ITT-LOCF) analysis, treatment with lorcaserin was associated withhighly statistically significant (p <0.0001) categorical and averageweight loss from baseline after 12 months: 47.5% of lorcaserin patientslost greater than or equal to 5% of their body weight from baselinecompared to 20.3% in the placebo group. This result satisfied theefficacy benchmark in the most recent FDA draft guidance. Average weightloss of 5.8% of body weight, or 12.7 pounds, was achieved in thelorcaserin group, compared to 2.2% of body weight, or 4.7 pounds, in theplacebo group. Statistical separation from placebo was observed by Week2, the first post-baseline measurement. 22.6% of lorcaserin patientslost greater than or equal to 10% of their body weight from baseline,compared to 7.7% in the placebo group. Lorcaserin patients who completed52 weeks of treatment according to the protocol lost an average of 8.2%of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in theplacebo group (p<0.0001).

In addition, the 5-HT_(2C) receptor is also involved in other diseases,conditions and disorders, such as, obsessive compulsive disorder, someforms of depression, and epilepsy. Accordingly, 5-HT_(2C) receptoragonists can have anti-panic properties, and properties useful for thetreatment of sexual dysfunction. In addition, 5-HT_(2C) receptoragonists are useful for the treatment of psychiatric symptoms andbehaviors in individuals with eating disorders such as, but not limitedto, anorexia nervosa and bulimia nervosa. Individuals with anorexianervosa often demonstrate social isolation. Anorexic individuals oftenpresent symptoms of being depressed, anxious, obsession, perfectionistictraits, and rigid cognitive styles as well as sexual disinterest. Othereating disorders include, anorexia nervosa, bulimia nervosa, bingeeating disorder (compulsive eating) and ED-NOS (i.e., eating disordersnot otherwise specified—an official diagnosis). An individual diagnosedwith ED-NOS possess atypical eating disorders including situations inwhich the individual meets all but a few of the criteria for aparticular diagnosis. What the individual is doing with regard to foodand weight is neither normal nor healthy.

The 5-HT_(2C) receptor plays a role in Alzheimer Disease (AD).Therapeutic agents currently prescribed for Alzheimer's disease (AD) arecholinomimetic agents that act by inhibiting the enzymeacetylcholinesterase. The resulting effect is increased levels ofacetylcholine, which modestly improves neuronal function and cognitionin patients with AD. Although, dysfunction of cholinergic brain neuronsis an early manifestation of AD, attempts to slow the progression of thedisease with these agents have had only modest success, perhaps becausethe doses that can be administered are limited by peripheral cholinergicside effects, such as tremors, nausea, vomiting, and dry mouth. Inaddition, as AD progresses, these agents tend to lose theireffectiveness due to continued cholinergic neuronal loss.

Therefore, there is a need for agents that have beneficial effects inAD, particularly in alleviating symptoms by improving cognition andslowing or inhibiting disease progression, without the side effectsobserved with current therapies. Therefore, serotonin 5-HT_(2C)receptors, which are exclusively expressed in brain, are attractivetargets.

Another disease, disorder or condition that can is associated with thefunction of the 5-HT_(2C) receptor is erectile dysfunction (ED).Erectile dysfunction is the inability to achieve or maintain an erectionsufficiently rigid for intercourse, ejaculation, or both. An estimated20-30 million men in the United States have this condition at some timein their lives. The prevalence of the condition increases with age. Fivepercent of men 40 years of age report ED. This rate increases to between15% and 25% by the age of 65, and to 55% in men over the age of 75years.

Erectile dysfunction can result from a number of distinct problems.These include loss of desire or libido, the inability to maintain anerection, premature ejaculation, lack of emission, and inability toachieve an orgasm. Frequently, more than one of these problems presentsthemselves simultaneously. The conditions may be secondary to otherdisease states (typically chronic conditions), the result of specificdisorders of the urogenital system or endocrine system, secondary totreatment with pharmacological agents (e.g. antihypertensive drugs,antidepressant drugs, antipsychotic drugs, etc.) or the result ofpsychiatric problems. Erectile dysfunction, when organic, is primarilydue to vascular irregularities associated with atherosclerosis,diabetes, and hypertension.

There is evidence for use of a serotonin 5-HT_(2C) agonist for thetreatment of sexual dysfunction in males and females. The serotonin5-HT_(2C) receptor is involved with the processing and integration ofsensory information, regulation of central monoaminergic systems, andmodulation of neuroendocrine responses, anxiety, feeding behavior, andcerebrospinal fluid production [Tecott, L. H., et al. Nature 374:542-546 (1995)]. In addition, the serotonin 5-HT_(2C) receptor has beenimplicated in the mediation of penile erections in rats, monkeys, andhumans.

In summary, the 5-HT_(2C) receptor is a validated and well-acceptedreceptor target for the prophylaxis and/or treatment of 5-HT_(2C)mediated receptor diseases and disorders, such as, obesity, eatingdisorders, psychiatric disorders, Alzheimer Disease, sexual dysfunctionand disorders related thereto. It can be seen that there exists a needfor selective 5-HT_(2C) receptor agonists that can safely address theseneeds. The present invention is directed to these, as well as other,important ends.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt, a pharmaceuticalcomposition, or a dosage form of the present invention.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

In some embodiments, the weight management comprises weight loss.

In some embodiments, the weight management comprises maintenance ofweight loss.

In some embodiments, the weight management comprises decreased foodconsumption.

In some embodiments, the weight management comprises increasingmeal-related satiety.

In some embodiments, the weight management comprises reducing pre-mealhunger.

In some embodiments, the weight management comprises reducing intra-mealfood intake.

In some embodiments, the weight management further comprises areduced-calorie diet.

In some embodiments, the weight management further comprises a programof regular exercise.

In some embodiments, the weight management further comprises both areduced-calorie diet and a program of regular exercise.

In some embodiments, the individual in need of weight management is anobese patient with an initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of weight management is anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition.

In some embodiments, the individual in need of weight management is anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧30 kg/m².

In some embodiments, the individual in need of weight management has aninitial body mass index ≧27 kg/m².

In some embodiments, the individual in need of weight management has aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance, and sleep apnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧25 kg/m².

In some embodiments, the individual in need of weight management has aninitial body mass index ≧25 kg/m² in the presence of at least one weightrelated comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧25 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance, and sleep apnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 20 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 20 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 21 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 21 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 22 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 22 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 23 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 23 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 24 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 24 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 25 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 25 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 26 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 26 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 27 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 27 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 28 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 28 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 29 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 29 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 30 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 30 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 31 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 31 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 32 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 32 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 33 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 33 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 34 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 34 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 35 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 35 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 36 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 36 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 37 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 37 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 38 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 38 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 39 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 39 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 40 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of weight management has aninitial body mass index ≧about 40 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the method for weight management further comprisesadministering phentermine to the individual.

One aspect of the present invention pertains to methods for thetreatment of a disorder related to 5-HT_(2C) receptor activity in anindividual, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

One aspect of the present invention pertains to methods for thetreatment of obesity, comprising administering to an individual in needthereof, a therapeutically effective amount of a salt or apharmaceutical composition of the present invention.

In some embodiments, the method for the treatment of obesity furthercomprises the administration or prescription of phentermine.

In some embodiments, the method for the treatment of obesity furthercomprises gastric electrical stimulation.

One aspect of the present invention pertains to methods for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

One aspect of the present invention pertains to methods for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual in preparation of the individual for bariatricsurgery, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

One aspect of the present invention pertains to methods for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual, comprising administering to an individual in needthereof, a therapeutically effective amount of a salt or apharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual following bariatric surgery, comprisingadministering to an individual in need thereof, a therapeuticallyeffective amount of a salt or a pharmaceutical composition of thepresent invention.

One aspect of the present invention pertains to methods for inducingsatiety in an individual, comprising administering to an individual inneed thereof, a therapeutically effective amount of a salt or apharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for decreasingfood intake in an individual, comprising administering to an individualin need thereof, a therapeutically effective amount of a salt or apharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for decreasinghunger in an individual, comprising administering to an individual inneed thereof, a therapeutically effective amount of a salt or apharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for decreasingfood cravings in an individual, comprising administering to anindividual in need thereof, a therapeutically effective amount of a saltor a pharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for increasingintermeal interval in an individual, comprising administering to anindividual in need thereof, a therapeutically effective amount of a saltor a pharmaceutical composition of the present invention.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: schizophrenia, anxiety,depression, psychoses and alcohol addiction, comprising administering toan individual in need thereof, a therapeutically effective amount of asalt or a pharmaceutical composition of the present invention.

In some embodiments, the disorder is schizophrenia.

In some embodiments, the disorder is anxiety.

In some embodiments, the disorder is depression.

In some embodiments, the disorder is psychoses.

In some embodiments, the disorder is alcohol addiction.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for weightmanagement in an individual.

In some embodiments, the weight management comprises weight loss.

In some embodiments, the weight management comprises maintenance ofweight loss.

In some embodiments, the weight management comprises decreased foodconsumption.

In some embodiments, the weight management comprises increasingmeal-related satiety.

In some embodiments, the weight management comprises reducing pre-mealhunger.

In some embodiments, the weight management comprises reducing intra-mealfood intake.

In some embodiments, the weight management further comprises areduced-calorie diet.

In some embodiments, the weight management further comprises a programof regular exercise.

In some embodiments, the weight management further comprises both areduced-calorie diet and a program of regular exercise.

In some embodiments, the individual is an obese patient with an initialbody mass index ≧30 kg/m².

In some embodiments, the individual is an overweight patient with aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition.

In some embodiments, the individual is an overweight patient with aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance, and sleep apnea.

In some embodiments, the individual has an initial body mass index ≧30kg/m².

In some embodiments, the individual has an initial body mass index ≧27kg/m².

In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid condition.

In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance, and sleep apnea.

In some embodiments, the individual has an initial body mass index ≧25kg/m².

In some embodiments, the individual has an initial body mass index ≧25kg/m² in the presence of at least one weight related comorbid condition.

In some embodiments, the individual has an initial body mass index ≧25kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance, and sleep apnea.

In some embodiments, the medicament for weight management is used incombination with phentermine.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for a disorderrelated to 5-HT_(2C) receptor activity in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for the treatmentof obesity in an individual.

In some embodiments, the treatment of obesity further comprises theadministration or prescription of phentermine.

In some embodiments, the treatment of obesity further comprises gastricelectrical stimulation.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual in preparation of the individual for bariatricsurgery.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual following bariatric surgery.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for inducingsatiety in an individual.

One aspect of the present invention pertains to the use of salts, orcrystalline forms of the present invention, in the manufacture of amedicament for decreasing food intake in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for decreasinghunger in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for decreasingfood cravings in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for increasingintermeal interval in an individual.

One aspect of the present invention pertains to the use of salts of thepresent invention, in the manufacture of a medicament for the treatmentof a disorder selected from: schizophrenia, anxiety, depression,psychoses and alcohol addiction in an individual.

In some embodiments, the disorder is schizophrenia.

In some embodiments, the disorder is anxiety.

In some embodiments, the disorder is depression.

In some embodiments, the disorder is psychoses.

In some embodiments, the disorder is alcohol addiction.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of treatment of a disorder related to5-HT_(2C) receptor activity in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of treatment of obesity in an individual.

In some embodiments, the method of treatment of obesity furthercomprises the administration or prescription of phentermine.

In some embodiments, the method of treatment of obesity furthercomprises gastric electrical stimulation.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of inducing weight loss, BMI loss, waistcircumference loss or body fat percentage loss in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of inducing weight loss, BMI loss, waistcircumference loss or body fat percentage loss in an individual inpreparation of the individual for bariatric surgery.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of maintaining weight loss, BMI loss,waist circumference loss or body fat percentage loss in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of maintaining weight loss, BMI loss,waist circumference loss or body fat percentage loss in an individualfollowing bariatric surgery.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of inducing satiety in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of decreasing food intake in anindividual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of decreasing hunger in an individual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of decreasing food cravings in anindividual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of increasing intermeal interval in anindividual.

One aspect of the present invention pertains to salts of the presentinvention, for use in a method of treatment of a disorder selected from:schizophrenia, anxiety, depression, psychoses and alcohol addiction inan individual.

In some embodiments, the disorder is schizophrenia.

In some embodiments, the disorder is anxiety.

In some embodiments, the disorder is depression.

In some embodiments, the disorder is psychoses.

In some embodiments, the disorder is alcohol addiction.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightloss.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method ofmaintenance of weight loss.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of decreasingfood consumption.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of increasingmeal-related satiety.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of reducingpre-meal hunger.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of reducingintra-meal food intake.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a reduced-calorie diet.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a program of regular exercise.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement further comprising a reduced-calorie diet and a program ofregular exercise.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an obese patient with an initial body mass index ≧30kg/m².

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an overweight patient with an initial body mass index ≧27kg/m² in the presence of at least one weight related co-morbidcondition.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an overweight patient with an initial body mass index ≧27kg/m² in the presence of at least one weight related co-morbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance, and sleep apnea.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧30 kg/m².

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m².

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related co-morbid condition.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related co-morbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m².

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m² inthe presence of at least one weight related co-morbid condition.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in an individual with an initial body mass index ≧25 kg/m² inthe presence of at least one weight related co-morbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in combination with phentermine.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof a disorder related to 5-HT_(2C) receptor activity in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof obesity in an individual.

In some embodiments, the method of treatment of obesity furthercomprises the administration or prescription of phentermine.

In some embodiments, the method of treatment of obesity furthercomprises gastric electrical stimulation.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual in preparation of the individual for bariatricsurgery.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method ofmaintaining weight loss, BMI loss, waist circumference loss or body fatpercentage loss in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method ofmaintaining weight loss, BMI loss, waist circumference loss or body fatpercentage loss in an individual following bariatric surgery.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of inducingsatiety in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of decreasingfood intake in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of decreasinghunger in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of decreasingfood cravings in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of increasingintermeal interval in an individual.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof a disorder selected from: schizophrenia, anxiety, depression,psychoses and alcohol addiction in an individual.

In some embodiments, the disorder is schizophrenia.

In some embodiments, the disorder is anxiety.

In some embodiments, the disorder is depression.

In some embodiments, the disorder is psychoses.

In some embodiments, the disorder is alcohol addiction.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a salt or a pharmaceuticalcomposition of the present invention.

In some embodiments, the weight management comprises one or more of:weight loss, maintenance of weight loss, decreased food consumption,increasing meal-related satiety, reducing pre-meal hunger, and reducingintra-meal food intake.

In some embodiments, the weight management is as an adjunct to diet andexercise.

In some embodiments, the individual in need of weight management isselected from: an obese patient with an initial body mass index ≧30kg/m²; an overweight patient with an initial body mass index ≧27 kg/m²in the presence of at least one weight related comorbid condition; anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition; wherein theweight related co-morbid condition is selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the method further comprises administering a secondanti-obesity agent to the individual.

In some embodiments, the second anti-obesity agent is selected from:chlorphentermine, clortermine, phenpentermine, and phentermine, andpharmaceutically acceptable salts, solvates, and hydrates thereof.

In some embodiments, the method further comprises administering ananti-diabetes agent to the individual.

In some embodiments, the anti-diabetes agent is metformin.

One aspect of the present invention pertains to uses of a salt of thepresent invention, in the manufacture of a medicament for weightmanagement in an individual.

In some embodiments, the weight management comprises one or more of:weight loss, maintenance of weight loss, decreased food consumption,increasing meal-related satiety, reducing pre-meal hunger, and reducingintra-meal food intake.

In some embodiments, the medicament is used as an adjunct to diet andexercise.

In some embodiments, the individual in need of weight management isselected from:

an obese patient with an initial body mass index ≧30 kg/m²; anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition; and anoverweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition; wherein theweight related co-morbid condition is selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

In some embodiments, the medicament is used in combination with a secondanti-obesity agent.

In some embodiments, the second anti-obesity agent is selected from:chlorphentermine, clortermine, phenpentermine, and phentermine, andpharmaceutically acceptable salts, solvates, and hydrates thereof.

In some embodiments, the medicament is used in combination with ananti-diabetes agent.

In some embodiments, the medicament is used in combination with ananti-diabetes agent; wherein the anti-diabetes agent is metformin.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement; wherein the weight management comprises one or more of:weight loss, maintenance of weight loss, decreased food consumption,increasing meal-related satiety, reducing pre-meal hunger, and reducingintra-meal food intake.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use as an adjunct to diet andexercise for weight management.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement; wherein the individual in need of weight management isselected from: an obese patient with an initial body mass index ≧30kg/m²; an overweight patient with an initial body mass index ≧27 kg/m²in the presence of at least one weight related comorbid condition; andan overweight patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition; wherein theweight related co-morbid condition is selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance, and sleepapnea.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in combination with a second anti-obesity agent.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in combination with a second anti-obesity agent selectedfrom: chlorphentermine, clortermine, phenpentermine, and phentermine,and pharmaceutically acceptable salts, solvates, and hydrates thereof.

One aspect of the present invention pertains to salts and pharmaceuticalcompositions of the present invention, for use in a method of weightmanagement in combination with an anti-diabetes agent; wherein theanti-diabetes agent is metformin.

Combination Therapies

The salts of the present invention can be used in combination withsuitable pharmaceutical agents.

In some embodiments the salts of the present invention can be used incombination with a second anti-obesity agent. Anti-obesity agentsinclude, for example, adrenergic reuptake inhibitors, apolipoprotein-Bsecretion/microsomal triglyceride transfer protein inhibitors, β3adrenergic receptor agonists, bombesin agonists, cannabinoid 1 receptorantagonists, cholescystokinin-A agonists, ciliary neutrotrophic factors,dopamine agonists, galanin antagonists, ghrelin receptor antagonists,glucagon-like peptide-1 receptor agonists, glucocorticoid receptoragonists or antagonists, histamine-3 receptor antagonists or reverseagonists, human agouti-related proteins, leptin receptor agonists,lipase inhibitors, MCR-4 agonists, melanin concentrating hormoneantagonists, melanocyte-stimulating hormone receptor analogs, monoaminereuptake inhibitors, neuromedin U receptor agonists, neuropeptide-Yantagonists, orexin receptor antagonists, stimulants, sympathomimeticagents, thyromimetic agents, and urocortin binding protein antagonists.

In some embodiments, the second anti-obesity agent is selected from:4-methylamphetamine, 5-HTP, amfecloral, amfepentorex, amfepramone,aminorex, amphetamine, amphetaminil, atomoxetine, benfluorex,benzphetamine, bromocriptine, bupropion, cathine, cathinone, cetilistat,chlorphentermine, ciclazindol, clobenzorex, cloforex, clominorex,clortermine, dapiclermin, dehydroepiandrosterone, dehydroepiandrosteroneanalogues, dexmethylphenidate, dextroamphetamine, dextromethamphetamine,difemetorex, dimethylcathinone, dinitrophenol, diphemethoxidine,ephedra, ephedrine, ethylamphetamine, etolorex, fenbutrazate,fencamfamine, fenethylline, fenproporex, fludorex, fluminorex,furfenorex, galactomannan, glucomannan, ibipinabant, indanorex, khat,L-dopa, leptin, a leptin analog, levopropylhexedrine, lisdexamfetamine,L-phenylalanine, L-tryptophan, L-tyrosine,N-[[trans-4-[(4,5-dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]methanesulfonamide,manifaxine, mazindol, mefenorex, metformin, methamphetamine,methylphenidate, naloxone, naltrexone, oleoyl-estrone, orlistat,otenabant, oxyntomodulin, P57, pemoline, peptide YY, phendimetrazine,phenethylamine, phenmetrazine, phenpentermine, phentermine,phenylpropanolamine, pipradrol, prolintane, propylhexedrine,pseudoephedrine, pyrovalerone, radafaxine, reboxetine, rimonabant,setazindol, sibutramine, simmondsin, sterculia, surinabant, synephrine,taranabant, tesofensine, topiramate, viloxazine, xylopropamine,yohimbine, zonisamide, and zylofuramine, and pharmaceutically acceptablesalts, solvates, and hydrates thereof.

In some embodiments, the second anti-obesity agent is selected from:4-methylamphetamine, amfecloral, amfepentorex, amfepramone, aminorex,amphetamine, amphetaminil, atomoxetine, benfluorex, benzphetamine,bupropion, cathine, cathinone, chlorphentermine, ciclazindol,clobenzorex, cloforex, clominorex, clortermine, dexmethylphenidate,dextroamphetamine, dextromethamphetamine, difemetorex,dimethylcathinone, diphemethoxidine, ephedra, ephedrine,ethylamphetamine, etolorex, fenbutrazate, fencamfamine, fenethylline,fenproporex, fludorex, fluminorex, furfenorex, indanorex, khat,levopropylhexedrine, lisdexamfetamine, manifaxine, mazindol, mefenorex,methamphetamine, methylphenidate, pemoline, phendimetrazine,phenethylamine, phenmetrazine, phenpentermine, phentermine,phenylpropanolamine, pipradrol, prolintane, propylhexedrine,pseudoephedrine, pyrovalerone, radafaxine, reboxetine, setazindol,sibutramine, synephrine, taranabant, tesofensine, viloxazine,xylopropamine, and zylofuramine, and pharmaceutically acceptable salts,solvates, and hydrates thereof.

In some embodiments, the second anti-obesity agent is selected from:chlorphentermine, clortermine, phenpentermine, and phentermine, andpharmaceutically acceptable salts, solvates, and hydrates thereof.

In some embodiments the salts of the present invention can be used incombination with an anti-diabetes agent. Anti-diabetes agents include,for example, DPP-IV inhibitors, biguanides, alpha-glucosidaseinhibitors, insulin analogues, sulfonylureas, SGLT2 inhibitors,meglitinides, thiazolidinediones, anti-diabetic peptide analogues, andGPR119 agonists.

In some embodiments, the anti-diabetes agent is selected from:sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin,phenformin, metformin, buformin, proguanil, acarbose, miglitol,voglibose, tolbutamide, acetohexamide, tolazamide, chlorpropamide,glipizide, glibenclamide, glimepiride, gliclazide, dapagliflozin,remigliflozin, sergliflozin, and4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

In some embodiments, the anti-diabetes agent is a DPP-IV inhibitorselected from the following compounds and pharmaceutically acceptablesalts, solvates, and hydrates thereof:3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile;(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile;2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile;8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine;1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid;4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile;1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one;(2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine;8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione;1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one;(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylicacid bis-dimethylamide;((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone;(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile;6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione;2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile;(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile;(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile;(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone;(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;and(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine.

In some embodiments, the anti-diabetes agent is an alpha-glucosidaseinhibitor selected from the following compounds and pharmaceuticallyacceptable salts, solvates, and hydrates thereof:(2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal;(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol;and(1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol.

In some embodiments, the anti-diabetes agent is a sulfonylurea selectedfrom the following compounds and pharmaceutically acceptable salts,solvates, and hydrates thereof:N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide);5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide;and3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide.

In some embodiments, the anti-diabetes agent is an SGLT2 inhibitorselected from the following compounds and pharmaceutically acceptablesalts, solvates, and hydrates thereof:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methylcarbonate; and ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methylcarbonate.

In some embodiments, the anti-diabetes agent is a meglitinide selectedfrom the following compounds and pharmaceutically acceptable salts,solvates, and hydrates thereof:(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoicacid;(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoicacid; and(S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoicacid.

In some embodiments, the anti-diabetes agent is a biguanide selectedfrom the following compounds and pharmaceutically acceptable salts,solvates, and hydrates thereof: metformin, phenformin, buformin, andproguanil.

In some embodiments, the anti-diabetes agent is metformin.

In some embodiments, the anti-diabetes agent is a GPR119 agonistselected from the GPR119 agonists disclosed in the following PCTapplications: WO2006083491, WO 2008081204, WO2009123992, WO2010008739,WO2010029089, and WO2010149684.

In some embodiments, the anti-diabetes agent is4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

In some embodiments, the anti-diabetes agent is5-(4-(4-(3-fluoro-4-(methylsulfonyl)phenoxy)butan-2-yl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole.

Other anti-obesity agents, and anti-diabetes agents including the agentsset forth infra, are well known, or will be readily apparent in light ofthe instant disclosure, to one of ordinary skill in the art. It will beunderstood that the scope of combination therapy of the salts of thepresent invention with other anti-obesity agents and with anti-diabetesagents is not limited to those listed above, but includes in principleany combination with any pharmaceutical agent or pharmaceuticalcomposition useful for the treatment of overweight, obese, and diabeticindividuals.

One aspect of the present invention pertains to salts of the presentinvention, characterized in that the salts is administered inconjunction with a second anti-obesity agent as described herein.

One aspect of the present invention pertains to salts of the presentinvention, characterized in that the salt is administered in conjunctionwith an anti-diabetes agent as described herein.

One aspect of the present invention pertains to salts of the presentinvention for use in combination with a second anti-obesity agent foruse in weight management.

One aspect of the present invention pertains to salts of the presentinvention for use in combination with an anti-diabetes agent for use inweight management and the treatment of diabetes.

One aspect of the present invention pertains to methods of weightmanagement in an individual in need thereof, comprising administering tothe individual a salt of the present invention and a second anti-obesityagent wherein the salt and the second anti-obesity agent areadministered to the individual simultaneously, separately, orsequentially.

One aspect of the present invention pertains to methods of weightmanagement and treating diabetes in an individual in need thereof,comprising administering to the individual a salt of the presentinvention and an anti-diabetes agent wherein the salt and theanti-diabetes agent are administered to the individual simultaneously,separately, or sequentially.

One aspect of the present invention pertains to methods of weightmanagement in an individual in need thereof, wherein the individual hasbeen or is being treated with a second anti-obesity agent, the methodcomprising administering to the individual a therapeutically effectiveamount of a salt of the present invention.

One aspect of the present invention pertains to methods of weightmanagement and treatment of diabetes in an individual in need thereof,wherein the individual has been or is being treated with ananti-diabetes agent, the method comprising administering to theindividual a therapeutically effective amount of a salt of the presentinvention.

One aspect of the present invention pertains to anti-obesity agents,characterized in that the anti-obesity agent is administered inconjunction with a salt of the present invention.

One aspect of the present invention pertains to anti-diabetes agents,characterized in that the anti-diabetes agent is administered inconjunction with a salt of the present invention.

One aspect of the present invention pertains to anti-obesity agents foruse in combination with a salt of the present invention for use inweight management.

One aspect of the present invention pertains to anti-diabetes agents foruse in combination with a salt of the present invention for use inweight management and the treatment of diabetes.

One aspect of the present invention pertains to methods of weightmanagement in an individual in need thereof, comprising administering tothe individual an anti-obesity agent and a salt of the present inventionwherein the anti-obesity agent and the salt are administered to theindividual simultaneously, separately, or sequentially.

One aspect of the present invention pertains to methods of weightmanagement and treating diabetes in an individual in need thereof,comprising administering to the individual an anti-diabetes agent and asalt of the present invention wherein the anti-diabetes agent and thesalt are administered to the individual simultaneously, separately, orsequentially.

One aspect of the present invention pertains to methods of weightmanagement in an individual in need thereof, wherein the individual hasbeen or is being treated with a salt of the present invention, themethod comprising administering to the individual a therapeuticallyeffective amount of a second anti-obesity agent.

One aspect of the present invention pertains to methods of weightmanagement and treatment of diabetes in an individual in need thereof,wherein the individual has been or is being treated with a salt of thepresent invention, the method comprising administering to the individuala therapeutically effective amount of an anti-diabetes agent.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

The following examples are provided to further define the inventionwithout, however, limiting the invention to the particulars of theseexamples. The compounds and salts thereof described herein, supra andinfra, are named according to the CS ChemDraw Ultra Version 7.0.1,AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7. In certaininstances common names are used and it is understood that these commonnames would be recognized by those skilled in the art.

Powder X-ray Diffraction (PXRD) studies were conducted using an X'PertPRO MPD powder diffractometer (PANalytical, Inc.; EQ0233) with a Cusource set at 45 kV and 40 mA, Cu(Kα) radiation and an X'Celeratordetector. Samples were placed on a PXRD sample plate either as-is orground slightly to reduce the size of large particles or crystals. Datawere collected with the samples spinning from 5° to 40° 20. Data wereanalyzed by X'Pert Data Viewer software, version 1.0a, to determinecrystallinity and/or crystal form, and by X'Pert HighScore software,version 1.0b, to generate the tables of PXRD peaks.

Differential scanning calorimetry (DSC) studies were conducted using aTA Instruments, Q2000 (EQ1980) at heating rate 10° C./min. Theinstruments were calibrated by the vendor for temperature and energyusing the melting point and enthalpy of fusion of an indium standard.

Thermogravimetric analyses (TGA) were conducted using a TA InstrumentsTGA Q5000 (EQ1982) at heating rate 10° C./min. The instrument wascalibrated by the vendor using Alumel and Nickel Curie points for thefurnace temperature and a standard weight for the balance.

Dynamic moisture-sorption (DMS) studies were conducted using a dynamicmoisture-sorption analyzer, VTI Corporation, SGA-100, equipment #0228.Samples were prepared for DMS analysis by placing 5 mg to 20 mg of asample in a tared sample holder. The sample was placed on the hang-downwire of the VTI balance. A drying step was run, typically at 40° C. and0.5-1% RH for 1-2 h. The isotherm temperature is 25° C. Defined % RHholds typically ranged from 10% RH to 90% RH or 95% RH, with intervalsof 10 to 20% RH. A % weight change smaller than 0.010% over a specifiednumber of minutes (typically 10-20), or up to 2 h, whichever occursfirst, is required before continuing to the next % RH hold. The watercontent of the sample equilibrated as described above was determined ateach % RH hold.

If saturated in water with excess solid, a deliquescing compound or saltthereof equilibrated in a closed system at a given temperature producesa % RH in that closed system that is equal to its deliquescing % RH(DRH) at that temperature. Fractional relative humidity is equal towater activity (a_(w)) in the vapor phase and at equilibrium in a closedsystem, the a_(w) in an aqueous solution is equal to the aw in the vaporphase above the solution (see Equation 1).

$\begin{matrix}\begin{matrix}{\frac{DRH}{100\%} = {\frac{\%\mspace{14mu}{RH}}{100\%}\left( {{above}\mspace{14mu}{enclosed}\mspace{14mu}{sat}\mspace{14mu}{aq}\mspace{14mu}{{sol}'}n\mspace{14mu}{at}\mspace{14mu}{equil}} \right)}} \\{= {a_{w}({vapor})}} \\{= {a_{w}({liquid})}}\end{matrix} & {{Equation}\mspace{14mu} 1}\end{matrix}$

A water activity meter was used to measure DRH for selected saltsdescribed herein. The instrument used for this study is a DecagonDevices AquaLab 4TE water activity meter, equipment #2169. Thisinstrument is designed with temperature control and a small headspaceabove the enclosed sample to establish equilibrium between solution andvapor phases quickly. Measured a_(w) values at 25° C. for samples ofaqueous-saturated Compound 1 salts with excess solid were multiplied by100% to get DRH values in % RH.

Acquity ultra performance liquid chromatography (UPLC) from Waters wasused for solubility and stoichiometry determination. Instrument numberis SY-EQ 1889. UPLC was equipped with Acquity PDA detector. UPLC mobilephase solvent A was 0.1% TFA in DI-water, solvent B was 0.1% TFA inacetonitrile. The mobile phase gradient as shown in the table below:

Time (min) Flow (mL/min) % A % B Curve 0.600 95.0 5.0 2.00 0.600 5.095.0 6 2.50 0.600 5.0 95.0 6 2.75 0.600 95.0 5.0 1 5.00 0.000 95.0 5.011

Column temperature was 40±5° C. Acquity UPLC® HSS T3 1.8 μm, 2.1×50 mmcolumn was used.

A known amount of sample was dissolved in water and analyzed by UPLC.The weight percent of Compound 1 in the salt samples was determined bycomparing the UV signal to that of a standard, Compound 1 hydrochloridesalt hemihydrate, or Compound 1 free base. The percentage of Compound 1or the percentage of the counterion determined was compared to thetheoretical values to establish the stoichiometry.

Example 1 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-Camsylate Salt (Compound 1 (1S)-(+)-10-Camsylate Salt, FormI)

The title salt was prepared by the dropwise addition of 1 moleequivalent of ˜3.6 M aqueous (1S)-(+)-10-camphorsulfonic acid to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile with vigorous stirring Immediate precipitation was observedand the solid was collected by filtration and washed with isopropylalcohol.

The DRH of the title salt was determined to be 99.8% RH by wateractivity measurement of a saturated aqueous solution with excess solidat 25° C., indicating that it was not deliquescent.

A known amount of the title salt was dissolved in water and analyzed byUPLC. The amount of Compound 1 in the salt sample was determined to be39.7%. This is slightly lower than the theoretical value, 45.7%.Solubility of the title salt in water was determined by UPLC to be 20mg/mL, with a final pH of 7.

The powder X-ray diffraction pattern of the title salt is shown inFIG. 1. Thermal analysis (TGA and DSC) of the title salt is shown inFIG. 2. DMS analysis of the title salt is shown in FIG. 3.

Example 2 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Hemi-L-malateSalt (Compound 1 Hemi-L-malate Salt, Form I)

The title salt was prepared by the dropwise addition of L-malic acid(0.5 eq.), either in solution in hot MeOH or as a solid, to a solutionof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inisopropyl acetate. The mixture was heated to ˜60° C. and held at thattemperature for ˜1 h. The mixture was then allowed to cool to roomtemperature and stirred for 1-3 days. The solid product was isolated byvacuum filtration and dried on the filter or in an oven at 40° C. for.An attempt to make a 1:1 salt produced a mixture of mono-L-malate andhemi-L-malate salts.

The DRH of the title salt was measured by water activity determinationfor a saturated aqueous solution with excess solid to be 89.9% RH at 25°C.

A known amount of the title salt was dissolved in water and analyzed byUPLC. The amount of Compound 1 in the sample was 76.5%. This is inacceptable agreement with the theoretical amount for a hemi-L-malatesalt of Compound 1, 74.5%. Aqueous solubility of the title salt was486.3 mg/mL, final pH 6.0.

The powder X-ray diffraction pattern of the title salt is shown in FIG.4. Thermal analysis (TGA and DSC) of the title salt is shown in FIG. 5.DMS analysis of the title salt is shown in FIG. 6.

Example 3 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-GlutamateSalt (Compound 1 L-Glutamate Salt, Form I)

Method 1

The title salt was prepared by addition of L-glutamic acid (0.5-1 eq.)in hot EtOH/H₂O (˜2:1) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate, followed by evaporation of the solvent overnight to produce asolid. The solid was slurried in isopropyl acetate and then isolated byfiltration.

Method 2

The title salt was prepared by addition of a solution of L-glutamic acid(1 eq.) in hot H₂O to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The productcrystallized without the need for evaporation or the solvent.

The products of both methods produced crystalline solids withessentially the same PXRD pattern.

The DRH of the title salt was measured by water activity determinationfor a saturated aqueous solution with excess solid to be 98.3% RH at 25°C.

A known amount of the title salt was dissolved in water and analyzed byUPLC. The amount of Compound 1 in the sample was 59-60%. This is inacceptable agreement with calculated amount, 57.1%. Aqueous solubilityof the title salt was 176.2 mg/mL, with a final pH 5.5.

The powder X-ray diffraction pattern of the title salt is shown in FIG.7. Thermal analysis (TGA and DSC) of the title salt is shown in FIG. 8.DMS analysis of the title salt is shown in FIG. 9.

Example 4 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-AspartateSalt (Compound 1 L-Aspartate Salt, Form I)

The title salt was prepared by addition of a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in eitheracetone or acetonitrile to one equivalent of aspartic acid solid. Themixture was heated to 50° C. then slow-cooled and stirred overnight.

A known amount of the title salt was dissolved in water and analyzed byUPLC. The amount of Compound 1 in the sample was 59.5%. This is in goodagreement with the theoretical value, 61.7%. Aqueous solubility of thetitle salt was 42 mg/mL. The final pH of a near saturated solution ofthis salt was 4.82.

The powder X-ray diffraction pattern of the title salt is shown in FIG.10. Thermal analysis (TGA and DSC) of the title salt is shown in FIG.11. DMS analysis of the title salt is shown in FIG. 12.

Example 5 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Hemimucate(Compound 1 Hemimucate Salt, Form I)

The title compound was synthesized from(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2equivalents) and mucic acid (1 equivalent) in THF, acetone or IPA (˜10mg/mL) with 4% water.

A known amount of Compound 1 hemimucate salt, was dissolved in methanoland analyzed by UPLC. The percent of Compound 1 in the salt sample wasdetermined to be 64.4%. This is close to the theoretical percentCompound 1 in a 1:0.5 Compound 1 hemimucate salt (65.1%).

The aqueous solubility of Compound 1 hemimucate was determined to be0.85 mg/mL at a pH of 1.48.

The powder X-ray diffraction pattern of the title salt is shown in FIG.13. Thermal analysis (TGA and DSC) of the title salt is shown in FIG.13. DMS analysis of the title salt is shown in FIG. 15.

Example 6 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine GlucuronateSalt (Compound 1 Glucuronate Salt, Form I)

The title salt was prepared by addition of a molar equivalent ofD-glucuronic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inisopropanol, acetonitrile, ethyl acetate, or acetone at 60° C.D-glucuronic acid, dissolved in the corresponding solvent at 60° C., wasadded dropwise with vigorous stirring. Precipitation occurredimmediately and the suspension was allowed to cool and stir overnight.The resulting solid was recovered by filtration and dried in a fume hoodovernight.

A known amount of Compound 1 glucuronate salt was dissolved in methanoland analyzed by UPLC. The percentage of Compound 1 in the salt samplewas determined to be 56.9%. This is slightly higher than the theoreticalpercentage of Compound 1 in an anhydrous Compound 1 glucuronate salt(50.2%).

The solubility of Compound 1 glucuronate in water was determined by UPLCto be 2.5 mg/mL, with a final pH of 6.80.

The powder X-ray diffraction pattern of the title salt is shown in FIG.16. Thermal analysis (TGA and DSC) of the title salt is shown in FIG.17. DMS analysis of the title salt is shown in FIG. 18.

Example 7 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine PyroglutamateSalt (Compound 1 Pyroglutamate Salt, Form I)

The title salt was prepared by combining one equivalent of pyroglutamicacid with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inethyl acetate at 60° C. then cooling slowly and stirring overnight. Theresulting white solid was isolated by filtration and dried.

A known amount of Compound 1 pyroglutamate was dissolved in methanol andanalyzed by UPLC. The percentage of Compound 1 in the salt sample wasdetermined to be 61.1%. This is close to the theoretical percentage ofCompound 1 in a 1:1 Compound 1 pyroglutamate salt, (60.3%).

The aqueous solubility of Compound 1 pyroglutamate was determined tobe >161.5 mg/mL at pH 3.94.

The powder X-ray diffraction pattern of the title salt is shown in FIG.19. Thermal analysis (TGA and DSC) of the title salt is shown in FIG.20. DMS analysis of the title salt is shown in FIG. 21.

Example 8 Preparation of Form I of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Di-camphorateSalt Solvate (Compound 1 Di-camphorate Salt Solvate, Form I)

The title salt was prepared by combining equal molar amounts of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and(1R,3S)-(+)-camphoric acid in ethyl acetate with 4% water. The solutionwas heated to 50° C. then slowly cooled. Upon cooling the sample was aclear solution and did not change after addition of MTBE. The sample wasevaporated to a clear oil which formed a white solid after standing atroom temperature.

A known amount of Compound 1 di-camphorate salt (solvated) was dissolvedin methanol and analyzed by UPLC. Percent of Compound 1 in the saltsample was determined to be 28.9%. This is close to the theoreticalpercent Compound 1 in a Compound 1 di-camphorate hydrate, 31.9%.

The aqueous solubility of Compound 1 di-camphorate salt solvate wasdetermined to be 38.6 mg/mL (12.3 mg/mL of the free base) at a pH of5.2.

The powder X-ray diffraction pattern of the title salt is shown in FIG.22. Thermal analysis (TGA and DSC) of the title salt is shown in FIG.23. DMS analysis of the title salt is shown in FIG. 24.

Example 9 Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideSalt Hemihydrate, Form III

Step A: Preparation of8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

To a reactor equipped with overhead agitation, jacket temperaturecontrol, a nitrogen inlet, and a caustic scrubber vent were charged, inthe specified order, 2-chloro-N-(4-chlorophenethyl)propan-1-aminehydrochloride (1.00 kg, 3.72 mol), aluminum chloride (0.745 kg, 5.58mol), and 1,2-dichlorobenzene (2.88 kg). The stirred reactor contentswere heated to 125-130° C., and stirring was continued at thattemperature for 14-18 h. At 60-70° C., a dark colored solution wasobtained. After reaction completion (<1.0% starting material by HPLCpeak area) had been verified, the stirred reactor contents were cooledto 30-35° C. To a second reactor vented to a caustic scrubber wascharged purified water (1.60 L) and silica gel (0.160 kg). TheFriedel-Crafts reaction mixture was transferred from the first reactorto the second reactor sufficiently slowly to maintain the stirredcontents of the second reactor at <60° C. After the transfer iscompleted, the next step may be executed without any hold period. Thesilica gel was filtered on a medium to coarse filter element at 55-60°C., and the filtered solids were subsequently washed with purified water(800 mL) preheated to 50-60° C. The combined mother and wash liquorfiltrates were cooled to 20-25° C. with vigorous agitation. Then thestirring was stopped, and the phases were allowed to separate at 20-25°C. (Process volume peaked at this point at 5.68 L). Three phasesseparated after 1-2 hours of standing. The lowest layer was drained towaste disposal. This dark layer consisted mostly of 1,2-dichlorobenzene(1.64 kg, 1.33 L) at pH 3-4. About 1% of the product was lost to thislayer. The remaining two phases were allowed to stand without agitationfor another 2-4 h. The lower layer was drained and saved (Layer A). Thislight colored phase (2.64 kg, 2.00 L, pH 2-3) contained ˜90%8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine. The upper layer(2.24 kg of a turbid water phase at pH 0-1) contains ˜1-4%8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine and remained in thereactor for back-extraction. The reactor was charged with cyclohexane(1.10 kg) and then 30% aqueous NaOH (2.44 kg, 18.3 mol). The resultingmixture (5.60 L) was stirred vigorously for 30 min at room temperature.The stirring was stopped, and the phases were allowed to separate for25-40 min. If the pH of the lower (aqueous) phase was ≧13, it wasdrained to waste disposal. Otherwise, more 30% aqueous NaOH was added,and this extraction was repeated. At pH 14, the aqueous phase contains<0.1% 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine free base. Theremaining upper (organic) phase from the reactor was drained and saved(Layer B). The reactor was rinsed with purified water and followed by asuitable organic solvent to remove residual salts. The lower,light-colored product phase (the middle of the original three phases,Layer A) and the upper phase (organic, Layer B) were returned to thereactor. To the stirred reactor contents was added 30% aqueous NaOH(1.60 kg, 12.0 mol). The reactor contents were stirred vigorously for0.5 hours. The stirring was discontinued and the phases were allowed toseparate over 15-30 minutes. The lower (aqueous) layer was drained towaste disposal. To the upper (organic) phase remaining in the reactorwas added purified water (2.40 kg). The reactor contents were stirredvigorously at 60-65° C. for 0.5 h. The stirring was discontinued, andthe phases were allowed to separate at 60-65° C. over 1.5-2 h. The lower(aqueous) layer was drained to waste disposal. With a reactor jackettemperature of 55-60° C., solvent from the upper (organic) layer wasremoved by vacuum distillation at pressures starting at 115-152 torr andfalling to 40 torr. The crude product,8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free base,was obtained as a yellow to brown oil distillation residue.

Step B: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HemitartrateSalt.

The distillation residue from Step A (crude8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free base)was dissolved in acetone (0.400 kg). The resulting solution was drainedand weighed to assay the8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine content by HPLC.Results of the assay were used to calculate charges of acetone,L-tartaric acid, and water. The quantities indicated below are typicalfor achievement of the target8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine:acetone:L-tartaricacid:water mole ratio of 1.00:9.6:0.25:3.6 prior to addition of seedcrystals. More acetone (1.415 kg) was added to the reactor and thestirred reactor contents were heated to 47-52° C. To the resultingsolution was added a solution of L-tartaric acid (0.1223 kg, 0.815 mol)in purified water (0.211 kg) at a steady rate over 5-15 min. A thinsuspension formed during the addition but then redissolved when themixture temperature was reestablished at 50° C. Hemitartrate seedcrystals (0.80 g) were added to the 50° C. solution to achievecloudiness and to initiate nucleation. Nucleation was allowed tocontinue for 2-3 h with agitation at 47-52° C. Acetone (0.473 kg) wasadded to the reactor while the stirred reactor contents were maintainedat 50° C. The resulting suspension was cooled to 0-5° C. slowly over 3-5h. Stirring was continued at 0° C. for another 1-3 h. The resultingwhite precipitate was collected on a medium-to-fine filter element andthen washed with a mixture of acetone (0.900 kg) and purified water(0.054 kg). The enantiomeric excess (ee) of the wet cake was determined.

If the ee was <98%, the wet cake was transferred back into the reactorand reslurried in a mixture of acetone (1.90 kg) and purified water(0.400 kg) at 55-60° C. for 0.5-1 h. If dissolution had not beenachieved after one h, then water (approximately 0.160 kg) was addeduntil a clear solution was achieved. The resulting mixture was thencooled to 0-5° C. slowly over 2-3 h. Stirring at 0° C. was continued foranother 3-5 h. The resulting white precipitate was collected on amedium-to-fine filter element and then washed with acetone (0.400 kg) at0-4° C.

The washed solid product (296 g wet) was dried at 60-65° C. under fullvacuum for 15-20 hours. The yield of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartratesalt, with about 99.7% ee and 7.5 wt. % water content, was 295 g (27.1%based on racemic 2-chloro-N-(4-chlorophenethyl)propan-1-aminehydrochloride and corrected for product water content).

Step C: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideSalt Hemihydrate, Form III.

To a reactor equipped with overhead agitation and a nitrogen inlet wascharged, in the specified order,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartrate(1.00 kg containing 7.5 wt % water, 1.71 mol), potassium carbonate(0.508 kg, 3.68 moles), ethyl acetate (2.68 kg), and purified water(2.68 kg). The resulting mixture was stirred at 20-25° C. for 30-40 min,and then the phases were allowed to separate over 0.5-1 h. The lower(aqueous) phase was drained to waste disposal. Purified water (2.68 kg)was added to the reactor, and the resulting mixture was vigorouslystirred for 10-20 min. The phases were allowed to separate over 1-1.5 h.The lower (aqueous) phase was drained to waste disposal. With thereactor contents at a temperature of 40-45° C., the solvent was removedby vacuum distillation at pressures falling from 153 torr to 46 torr.The residue was cooled to 20-25° C. Ethyl acetate (3.81 kg) was chargedto the reactor, and the distillation residue was dissolved withstirring. The water content of the resulting solution was verified byKarl Fischer analysis to be <0.8 wt. %. The solution was filteredthrough a polishing filter. The reactor was rinsed through the filterwith ethyl acetate (2.33 kg) previously verified by Karl Fischeranalysis to have <0.05 wt. % water content. Both the solution and rinsefiltrates were charged back into the reactor. Purified water (39.9 g)was added to the reactor. The stirred reactor contents were cooled to0-5° C., and then HCl gas (19.0 g, 0.521 mol) was added while thestirred reactor contents were maintained at 0-5° C.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridesalt hemihydrate seed crystals (1.33 g) were added to the stirredreactor contents to initiate nucleation at 0-5° C. The remaining HCl gas(107.6 g, 2.95 mol) was charged to the reactor at a steady rate over atleast 1.5-2 h while the stirred reactor contents were maintained at 0-5°C. The resulting suspension was stirred at 0-5° C. for 2 h. Theresulting white precipitate was collected on a medium-to-fine filterelement. The reactor and then the filtered solid product were washedwith ethyl acetate (1.33 kg). The wet cake (ca. 867 g) was dried at fullvacuum and 33-37° C. for 20 h or until the cake temperature had beenstable for 4 hours, whichever occurred first. The resulting(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridesalt hemihydrate (3.7 wt. % water content, 14.7% chloride content,<0.01% ROI, >99.6% ee, >99% HPLC purity, and <0.1% wrong isomer content)was obtained in a yield of about 741 g (89.9%).

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention.

The invention claimed is:
 1. A salt selected from:(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1S)-(+)-10-camsylate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineL-glutamate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt;(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt; and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt; and pharmaceutically acceptable solvates and hydratesthereof.
 2. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt.
 3. The salt according to claim 2, having anX-ray powder diffraction pattern comprising peaks, in terms of 2θ, atabout 18.25°, about 16.45°, and about 18.57°.
 4. The salt according toclaim 2, having an X-ray powder diffraction pattern substantially asshown in FIG.
 1. 5. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt.
 6. The salt according to claim 5, having an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 10.84°,about 11.7932°, and about 21.97°.
 7. The salt according to claim 5,having an X-ray powder diffraction pattern substantially as shown inFIG.
 4. 8. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt.
 9. The salt according to claim 8, having an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 25.59°,about 17.63°, and about 21.78°.
 10. The salt according to claim 8,having an X-ray powder diffraction pattern substantially as shown inFIG.
 7. 11. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt.
 12. The salt according to claim 11, having an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 21.22°,about 8.49°, and about 13.40°.
 13. The salt according to claim 11,having an X-ray powder diffraction pattern substantially as shown inFIG.
 10. 14. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucatesalt.
 15. The salt according to claim 14, having an X-ray powderdiffraction pattern comprising a peak, in terms of 2θ, at about 5.06°,about 18.60°, and about 20.92°.
 16. The salt according to claim 14,having an X-ray powder diffraction pattern substantially as shown inFIG.
 13. 17. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronatesalt.
 18. The salt according to claim 17, having an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 16.46°,about 5.59°, and about 18.40°.
 19. The salt according to claim 17,having an X-ray powder diffraction pattern substantially as shown inFIG.
 16. 20. The salt according to claim 1, that is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt.
 21. The salt according to claim 20, having an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 6.78°,about 18.80°, and about 16.95°.
 22. The salt according to claim 20,having an X-ray powder diffraction pattern substantially as shown inFIG.
 19. 23. A pharmaceutical composition comprising a salt according toclaim 1 and a pharmaceutically acceptable carrier.
 24. A process forpreparing a pharmaceutical composition comprising admixing a saltaccording to claim 1 and a pharmaceutically acceptable carrier.